U.S. patent application number 16/858599 was filed with the patent office on 2020-12-10 for purgeable pharmaceutical fill needle.
The applicant listed for this patent is VANRX PHARMASYSTEMS INC.. Invention is credited to Marcin CICHY, Carlos Alberto DIAZ GEURRERO, Juvenal NAING.
Application Number | 20200384455 16/858599 |
Document ID | / |
Family ID | 1000005046742 |
Filed Date | 2020-12-10 |
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United States Patent
Application |
20200384455 |
Kind Code |
A1 |
CICHY; Marcin ; et
al. |
December 10, 2020 |
PURGEABLE PHARMACEUTICAL FILL NEEDLE
Abstract
The present invention involves a fill needle system for
aseptically dispensing a pharmaceutical fluid in an aseptic chamber
comprises a fill needle tubing in fluid communication with a
pharmaceutical fluid source via flexible tubing and extending
through a fill needle hub; a fill needle dispensing tip disposed at
a dispensing end of the fill needle tubing; a fill needle sheath
shaped and arranged to removably mate with and seal aseptically to
the fill needle hub to form an aseptically sealed volume enclosing
the dispensing tip; and a fluid pressure pulse induction system
disposed and configured to compress the flexible tubing in order to
dislodge droplets of pharmaceutical fluid retained on the
dispensing tip after halting dispensing of the pharmaceutical
fluid. An associated method of dispensing pharmaceutical fluid
comprises operating the fluid pressure pulse induction system to
dislodge the droplets. The system may comprise a controller for
automatically controlling the dispensing and droplet
dislodging.
Inventors: |
CICHY; Marcin; (Surrey,
CA) ; NAING; Juvenal; (Belcarra, CA) ; DIAZ
GEURRERO; Carlos Alberto; (Burnaby, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VANRX PHARMASYSTEMS INC. |
BURNABY |
CA |
US |
|
|
Family ID: |
1000005046742 |
Appl. No.: |
16/858599 |
Filed: |
April 25, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16185035 |
Nov 9, 2018 |
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16858599 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01L 2300/0609 20130101;
B65B 3/04 20130101; B01L 2400/0487 20130101; B01L 2200/141
20130101; B01L 2200/026 20130101; B65B 55/12 20130101; B01L
2300/0832 20130101; B65B 3/003 20130101; G01N 2035/00148 20130101;
A61L 2/24 20130101; G01N 2035/00277 20130101; B01L 2200/0689
20130101; C12M 37/02 20130101; G01N 35/0099 20130101; G01N 35/10
20130101; B01L 1/025 20130101; B01L 1/04 20130101; C12M 41/14
20130101; A61L 2/16 20130101; B25J 21/00 20130101; A61J 1/12
20130101; G01N 35/00029 20130101; A61L 2/07 20130101; B01L 3/02
20130101; A61J 1/14 20130101; C12M 29/00 20130101; A61J 1/20
20130101 |
International
Class: |
B01L 1/02 20060101
B01L001/02; A61L 2/07 20060101 A61L002/07; A61L 2/16 20060101
A61L002/16; A61L 2/24 20060101 A61L002/24; B25J 21/00 20060101
B25J021/00; C12M 1/00 20060101 C12M001/00; C12M 1/12 20060101
C12M001/12; A61J 1/12 20060101 A61J001/12; A61J 1/14 20060101
A61J001/14; A61J 1/20 20060101 A61J001/20; B01L 1/04 20060101
B01L001/04; B01L 3/02 20060101 B01L003/02; B65B 3/00 20060101
B65B003/00; B65B 3/04 20060101 B65B003/04; B65B 55/12 20060101
B65B055/12; G01N 35/00 20060101 G01N035/00; G01N 35/10 20060101
G01N035/10 |
Claims
1. fill needle system for aseptically dispensing a pharmaceutical
fluid in a chamber capable of maintaining an aseptic condition, the
system comprising: a fill needle hub, a fill needle tubing in fluid
communication with a pharmaceutical fluid source via flexible
tubing and extending through the fill needle hub; a fill needle
dispensing tip disposed at a dispensing end of the fill needle
tubing; a fill needle sheath shaped and arranged to removably mate
with and seal aseptically to the fill needle hub to form an
aseptically sealed volume enclosing the dispensing tip; and a fluid
pressure pulse induction system disposed and configured to compress
the flexible tubing.
2. The system of claim 1, further comprising a controller
configured to control the dispensing of the pharmaceutical fluid
via the dispensing tip.
3. The system of claim 1, wherein the controller is configured to
operate the fluid pressure pulse induction system to automatically
compress the flexible tubing after halting dispensing of the
pharmaceutical fluid.
4. The system of claim 1, wherein the controller is configured to
induce in the fill needle tubing a pressure pulse of predetermined
fluid amplitude and duration.
5. The system of claim 1, wherein the fluid pressure pulse
induction system is disposed and configured to annularly compress
the flexible tubing.
6. The system of claim 1, wherein the fluid pressure pulse
induction system is one of piezoelectrically actuated,
electromechanically actuated, magnetically actuated, and
pneumatically actuated.
7. A fill needle for aseptically dispensing a pharmaceutical fluid
in a chamber capable of maintaining an aseptic condition, the
chamber having a pharmaceutical fluid source and a fluid pressure
pulse induction system with associated flexible tubing, the fill
needle comprising: a fill needle hub, a fill needle tubing in fluid
communication with the pharmaceutical fluid source and extending
through the fill needle hub; a fill needle dispensing tip disposed
at a dispensing end of the fill needle tubing; a fill needle sheath
shaped and arranged to removably mate with and seal aseptically to
the fill needle hub to form an aseptically sealed volume enclosing
the dispensing tip; and a fill needle fluid ejector operably
coupled to the fluid pressure induction system for manipulating the
dispensing of the pharmaceutical fluid through the fill needle
dispensing tip.
8. The fill needle of claim 7, wherein the chamber includes a
controller and further comprising a actuator configured to control
the dispensing of the pharmaceutical fluid via the dispensing tip
upon activation by the controller.
9. The fill needle of claim 8, wherein the controller is configured
to operate the fluid pressure pulse induction system to
automatically compress the flexible tubing after halting dispensing
of the pharmaceutical fluid.
10. The fill needle of claim 7, wherein the fluid pressure pulse
inducer is one of piezoelectrically actuated, electromechanically
actuated, magnetically actuated, and pneumatically actuated.
11. The fill needle of claim 7, wherein the fill needle fluid
ejector includes a vibration actuator.
12. The fill needle of claim 11, wherein the fill needle fluid
ejector includes hydrophobic material proximate the vibration
actuator.
13. The fill needle of claim 7, wherein the fill needle fluid
ejector includes a gas injector.
14. The fill needle of claim 13, wherein the fill needle fluid
ejector includes hydrophobic material proximate the gas
injector.
15. The fill needle of claim 7, wherein the fill needle fluid
ejector includes a mechanism for squeezing the fill needle
tubing.
16. The fill needle of claim 15, wherein the fill needle fluid
ejector further includes a bladder.
17. The fill needle of claim 16, wherein the fill needle fluid
ejector injects gas into the bladder.
18. The fill needle of claim 17, wherein the bladder is disposed
around the fill needle tubing proximate the fill needle dispensing
tip.
19. The fill needle of claim 7, wherein the fill needle fluid
ejector includes a levered piezoelectric actuator.
20. The fill needle of claim 19, wherein the fill needle fluid
ejector includes a bladder, and the levered piezoelectric actuator
is disposed to compress the bladder upon actuation.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional of U.S. patent
application Ser. No. 16/185,035, filed Nov. 18, 2018. The subject
matter of this application relates to that disclosed in U.S. patent
application Ser. No. 14/890,223, filed Jul. 22, 2011 which is a US
National Phase Entry of PCT Application No. PCT/US2012/047765,
filed Jul. 20, 2012, which claims priority to provisional
application 61/510,780, filed Jul. 22, 2011. This application also
relates to that disclosed in U.S. patent application Ser. No.
15/375,019, filed Dec. 9, 2016, which claims priority to
provisional application Ser. No. 62/265,938, filed Dec. 10, 2015.
This application is a continuation-in-part of PCT International
Patent Application No. PCT/CA2017/051071, filed Sep. 12, 2017,
which claims priority to U.S. patent application Ser. No.
15/647,633, filed Jul. 12, 2017; U.S. patent application Ser. No.
15/465,516, filed Mar. 21, 2017; and U.S. patent application Ser.
No. 15/264,554, filed Sep. 13, 2016. This application is also a
continuation-in-part of U.S. patent application Ser. No.
15/729,655, filed Oct. 10, 2017. The disclosures of all of these
applications are herein incorporated by reference herein.
TECHNICAL FIELD
[0002] This present invention relates to the medical field as
exemplified by IPC class A61 and more particularly to apparatus and
associated methods for sterilization of and sterile handling of
pharmaceutical materials and containers for pharmaceuticals,
including bringing pharmaceuticals into form for administration to
medical or veterinary patients. In one aspect, it relates to the
programmed and automatic operation of such apparatus configured and
arranged for filling pharmaceutical containers with predetermined
amounts of liquid or other materials.
BACKGROUND
[0003] Controlled environment enclosures are known in the art. Such
enclosures are used, for example, for containment of hazardous
materials. In other examples controlled environment enclosures are
used to provide controlled environments with limited numbers of
particulates.
[0004] In the art controlled environment enclosures are typically
fitted with ports for transfer of materials in and out of the
enclosure and the ports are fitted with gloves for manual
manipulation of equipment, parts or materials inside the enclosure.
Such gloves are subject to significant risk of puncture.
[0005] In some examples known in the art the controlled environment
enclosure is also used to limit exposure to viable particulates.
Such controlled environment enclosures may be required for aseptic
processing of cell cultures and for the manufacture of
pharmaceutical products, medical devices, food or food ingredients.
In these cases it is a requirement that the controlled environment
enclosure be decontaminated. This may be done thermally using steam
or chemically using chemical agents. Suitable chemical agents known
in the art include hydrogen peroxide, ozone, beta-propiolactone,
aziridine, formaldehyde, chlorine dioxide, ethylene oxide,
propylene oxide, and peracetic acid. In most cases the
decontamination and sterilization operations have to be preceded by
a cleaning process. Such cleaning processes have the function of
removing major contamination by simple mechanical and chemical
action.
[0006] In some examples in the prior art the controlled environment
also contains automated equipment. Such automated equipment
includes machines for filling of vials. The automated equipment
located in the controlled environment is typically of such a size
and complexity that it cannot be operated fully automatically
without human intervention. Such human intervention typically
requires the use of gloves with the associated risk of
puncture.
[0007] Fluid paths within the controlled environment enclosures may
be made from flexible tubing materials and may therefore have
significant gas permeability. Gases that naturally occur in air,
such as oxygen and carbon dioxide, as well as chemical
decontamination agents are known to diffuse into these tubing
materials. Accumulation of these agents in flexible tubing and
subsequent delayed release may be a major contamination problem
during operation. This applies in particular to products or
solutions that are sensitive to exposure to alkylating agents,
oxidizers, radicals or carbon dioxide. A typical example of human
intervention involving the use of gloves is the installation of the
fluid path or multiple fluid paths after the completion of
decontamination.
[0008] In view of the above there remains a need for controlled
environments that do not require human intervention via the use of
gloves and in which pharmaceutical fluids may be accurately and
aseptically dispensed into containers. In the present era of very
expensive pharmaceuticals, designer drugs, and customized gene
therapy preparations, it has become extremely important to
aseptically dispense pharmaceutical fluids at very precise volumes
into pharmaceutical containers. This is made all the more important
by the fact that these pharmaceuticals are very expensive and are
often provided in small volumes. At such low volumes, the amounts
of pharmaceutical fluid retained in fill needles at the end of
dispensing cycles may be a significant fraction of the total
dispensed amount, and the same is true of unreleased droplets of
fluid remaining pendant at the tip of the fill needle.
SUMMARY OF THE INVENTION
[0009] In one aspect of the invention there is provided a method
for installing a fluid path within a controlled environment
enclosure comprising, protecting the fluid path against an
environment external to the fluid path; introducing the fluid path
into the controlled environment enclosure; decontaminating the
controlled environment enclosure; and mechanically unprotecting the
fluid path within the controlled environment enclosure. The
mechanically unprotecting may be by a robotic arm manipulation
system. The decontaminating the controlled environment enclosure is
automatically done after the introducing the fluid path into the
controlled environment enclosure. The unprotecting is automatically
done after the decontaminating the controlled environment
enclosure.
[0010] In one aspect of the invention there is provided a method
for transferring within a controlled environment enclosure a fluid
along a fluid path to a destination within the controlled
environment enclosure, comprising protecting the fluid path against
an environment external to the fluid path; introducing the fluid
path into the controlled environment enclosure; decontaminating the
controlled environment enclosure; mechanically unprotecting the
fluid path within the controlled environment enclosure; and
transferring the fluid to the destination along the fluid path. The
mechanically unprotecting may be by a robotic arm manipulation
system. The fluid path may comprise a pre-sterilized tube. The
method may further comprise filtering the fluid in the fluid path
and the filtering may be sterile filtering. The destination may be
at least one of a culture of cells, a culture of tissue, an enzyme
solution, a suspension of immobilized enzymes, a mix of active
ingredients, and an excipient. The fluid may be an aseptic fluid.
The controlled environment enclosure may be an isolator. The
destination may be microwell plates or containers for
pharmaceutical products.
[0011] In one aspect of the invention there is provided a method
for uninstalling a fluid path from a controlled environment
enclosure, comprising mechanically protecting the fluid path within
the controlled environment enclosure; decontaminating the
controlled environment enclosure; opening the controlled
environment enclosure; and removing the fluid path from the
controlled environment enclosure. The mechanically protecting may
be by a robotic arm manipulation system. The decontaminating the
controlled environment enclosure may be done automatically after
the protecting the fluid path. The opening the controlled
environment enclosure may be done automatically after the
decontaminating the controlled environment enclosure.
[0012] In one aspect of the invention there is provided a method
for decontaminating a controlled environment enclosure having a
fluid path, the method comprising mechanically protecting by a
robotic action the fluid path within the controlled environment
enclosure; decontaminating the controlled environment enclosure;
and opening and closing the controlled environment enclosure. The
opening and closing the controlled environment enclosure may be
done before or after the decontaminating the controlled environment
enclosure. The mechanically protecting may be by a robotic arm
manipulation system. The decontaminating the controlled environment
enclosure may be done automatically after the mechanically
protecting the fluid path.
[0013] In one aspect of the invention there is provided an
apparatus for protection and unprotection of a fluid path within a
controlled environment enclosure that includes a fluid path
terminated by a fill needle with removable sheath, and a remotely
operated manipulation system for protection and/or unprotection of
the fluid path. The remotely operated manipulation system may
include a robotic arm manipulation system. The apparatus may
further include a tamper-evident device positioned to reveal a
breach of seal between the sheath and the fill needle. The
apparatus may further include a removal station that includes a
surface operative to interact with part of the sheath. The remotely
operated manipulation system may include a robot end tool including
at least one surface that is shaped to hold the fill needle. The
fluid path may be a pre-sterilized unit.
[0014] In one aspect of the invention there is provided an
apparatus for installing a fluid path within a controlled
environment enclosure that includes means for conveying the fluid,
and remotely operated means for protecting and/or unprotecting the
means for conveying the fluid.
[0015] The inventors envision that compact and well-designed
automated equipment may be operated inside closed controlled
environments without the use of any gloves, eliminating thereby the
risk of leaky gloves. The invention provides a method of installing
a fluid path inside a controlled environment enclosure without the
use of gloves. This requires the fluid path to be protected during
the decontamination process and to be unprotected prior to the use
of the fluid path. Furthermore, the fluid path may be automatically
closed after use.
[0016] The closed fluid path may be re-opened and re-used at a
later time. This may be useful for continuing the use of the fluid
path after unplanned events that require breaking of the integrity
of the enclosed controlled environment. Additionally, the closing
of the fluid path may be particularly useful in situations where
the fluid path has been in use for transfer of hazardous
substances. After closing of the fluid path, the enclosed
environment may be cleaned and decontaminated; after which the
fluid path may be removed.
[0017] In a first aspect of the invention a fluid handling assembly
is provided for automatically carrying out a fluid handling process
in an aseptic environment, the assembly comprising a first sheath
portion including an implement portion disposed within the first
sheath portion for use in the process, a first locking mechanism
portion, and a first sealing portion; a second sheath portion
including a second locking mechanism portion configured to mate
with positive detent with the first locking mechanism portion, and
a second sealing portion disposed to aseptically seal with the
first sealing portion when the first and second locking mechanism
portions are mutually mated, wherein the first and second sheath
portions define a sealed cavity that aseptically encapsulates the
implement portion when the first and second locking mechanism
portions are mutually mated. The assembly may be a fill assembly
and the implement portion comprises a proximal dispensing portion
of a fill needle, the fill needle including a fluid conduit that
extends through the first sheath portion to a distal fluid supply
end so that, when the first and second locking mechanism portions
are mutually mated, the proximal dispensing portion of the fill
needle is located inside the cavity and the distal fluid supply end
of the fluid conduit is located outside the cavity. The fluid
conduit may include a flexible tube in fluid communication with the
proximal dispensing portion of the fill needle. The assembly may be
a swab assembly with the implement portion comprising a swab
disposed inside the cavity when the first and second locking
mechanism portions are mutually mated.
[0018] The assembly may further comprise a controlled environment
enclosure configured to aseptically isolate the process and hold
the fluid handling assembly, and an articulated robot arm disposed
within the enclosure to manipulate the fluid handling assembly. The
first and second sheath portions may respectively comprise first
and second engagement portions. The assembly may further comprise a
robotic arm endpiece for the robotic arm, the endpiece configured
to bear the first sheath portion by engagement with positive detent
with the first engagement portion and a holding station comprising
a first holding fixture to hold the second sheath portion, the
fixture configured for engaging with the second engagement portion.
The holding station may comprise angled fingers disposed to engage
with the second engagement portion of the second sheath portion to
release the first sheath portion from the second sheath portion.
The holding station may comprise a second holding fixture
configured to suspend the mutually engaged first and second sheath
portions.
[0019] The first and second sheath portions may be separate
injection molded parts and wherein the locking mechanism portions
include at least one integrally molded spring member. The assembly
may further include a tamper indicator that is mechanically linked
to one of the locking mechanism portions and includes a portion
that is constructed to irreversibly tear in response to the
mechanical separation of the first and second sealing surfaces.
[0020] The first and second locking mechanism portions may be
configured to mutually mate when the first and second locking
mechanism portions are moved towards each other along a locking
axis. The first sheath portion may further include a first bearing
surface positioned at least generally normal to the locking axis,
and the second sheath portion may further include a second bearing
surface positioned at least generally normal to the locking axis
and facing the first bearing surface.
[0021] In a further aspect a method is provided for automatically
carrying out a fluid handling process in controlled environment
enclosure, the method comprising providing a first implement inside
a first sealed sheath, the first sheath sealed by a detent-based
sealing mechanism on the first sheath that keeps the first sheath
aseptically sealed around the first implement; placing the first
sheath in the controlled environment enclosure; decontaminating the
controlled environment enclosure around the first sheath after the
step of placing; actuating the sealing mechanism to open the first
sheath, and carrying out at least one step in the fluid handing
process with the implement in the controlled environment enclosure.
The step of providing may include providing a fill needle and
wherein the step of carrying out includes carrying out a fill
operation. The step of decontaminating may take place before the
step of carrying out a fill operation, further including a step of
again actuating the sealing mechanism to seal the first sheath.
[0022] The method may further include an additional step of
decontaminating the controlled environment chamber after the steps
of carrying out a fill operation and again actuating the sealing
mechanism. The method may yet further include providing a swab
inside a second sealed sheath, providing a second detent-based
sealing mechanism on the second sheath that keeps the second sheath
sealed around the swab, placing the second sheath in the controlled
environment enclosure, wherein the step of decontaminating
decontaminates the outside of the second sheath, and swabbing the
fill needle after the step of carrying out a fill operation.
[0023] The method may further include the steps of removing the
first implement and the first sheath from the controlled
environment enclosure, discarding the first implement and the first
sheath, providing a second implement inside a second sealed sheath,
providing a second detent-based sealing mechanism on the second
sheath that keeps the second sheath sealed around the second
implement, placing the second sheath in the controlled environment
enclosure, decontaminating the controlled environment enclosure
around the second sheath, and carrying out at least one step in
another run of the fluid handing process with the implement in the
aseptic environment.
[0024] The steps of actuating the first sealing mechanism and
carrying out the filling operation may be performed at least in
part by a robotic arm disposed within the controlled environment
enclosure. The method may further include the step of providing a
pre-sterilized tube aseptically sealed to the fill needle. The step
of carrying out a fill operation may include transferring fluid to
at least one of a culture of cells, a culture of tissue, an enzyme
solution, a suspension of immobilized enzymes, a mix of active
ingredients, and an excipient. The step of carrying out a fill
operation may include transferring fluid to at least one of
microwell plates and containers for pharmaceutical products.
[0025] In a further aspect, a method is provided for automatically
carrying out a fluid handling process in controlled environment
enclosure, comprising: providing a plurality of disposable
implements each aseptically sealed inside one of a plurality of
disposable sheaths, placing a first of the plurality of sealed
sheaths that contains a first of the plurality of implements in the
controlled environment enclosure, decontaminating the controlled
environment enclosure around the first sheath after the step of
placing the first sheath, opening the first sheath, carrying out at
least one step in the fluid handing process with the first
implement in the controlled environment enclosure, removing the
first sheath and the first implement from the controlled
environment enclosure, discarding the first implement and the first
sheath, placing a second of the plurality of sealed sheaths that
contains a second of the plurality of implements in the controlled
environment enclosure, decontaminating the controlled environment
enclosure around the second sheath after the step of placing the
second sheath, opening the second sheath, carrying out at least one
step in another run of the fluid handing process with the second
implement in the controlled environment, and repeating the steps of
placing, decontaminating, opening, removing, and discarding for
successive further ones of the plurality of disposable implements
and corresponding ones of the plurality of disposable sheaths. The
step of providing may provide a plurality of disposable implements
that each include an intact tamper indicator. The steps of placing
the first, second, and further sheaths may each include placing the
intact tamper indicator for the sheath being placed, and the steps
of opening the first, second, and further sheaths may each include
disrupting the tamper indicator for the sheath being opened.
[0026] In a further aspect, a fluid handling assembly is provided
for automatically carrying out a fluid handling process in an
aseptic environment, comprising: a first sheath portion including
an implement portion disposed within the first sheath portion for
use in the process, a first locking mechanism portion, a first
sealing portion, and a first bearing surface positioned at least
generally normal to a locking axis; a second sheath portion
including: a second locking mechanism portion configured to mate
with the first locking mechanism portion when the first and second
locking mechanism portions are moved towards each other along the
locking axis, a second sealing portion disposed to aseptically seal
with the first sealing portion when the first and second locking
mechanism portions are mutually mated, and a second bearing surface
positioned at least generally normal to the locking axis and facing
toward the first bearing surface, wherein the first and second
sheath portions define a sealed cavity that aseptically
encapsulates the implement portion when the first and second
locking mechanism portions are mutually mated.
[0027] In a further aspect, a fluid handling assembly is provided
for automatically carrying out a fluid handling process in an
aseptic environment, comprising: a first sheath portion including a
swab disposed within the first sheath portion for use in the
process, and a first sealing portion; and a second sheath portion
including a second sealing portion disposed to aseptically seal
with the first sealing portion, wherein the first and second sheath
portions define a sealed cavity that aseptically encapsulates the
swab when the first and second sealing portions are mutually
mated.
[0028] In a further aspect, a method is provided for automatically
carrying out a fluid handling process in controlled environment
enclosure, comprising: providing a swab inside a first aseptically
sealed sheath, placing the first sheath in the controlled
environment enclosure, decontaminating the controlled environment
enclosure around the first sheath after the step of placing,
opening the first sheath, and swabbing an implement used in the
fluid handing process with the swab in the controlled environment
enclosure.
[0029] In another aspect, a method is provided for aseptically
filling a pharmaceutical container with a pharmaceutical fluid, the
method comprising: in a chamber capable of maintaining an aseptic
condition providing a fill needle comprising a fill needle tubing
having a dispensing tip; establishing in the chamber an aseptic
condition; providing in the chamber at least one aseptic
pharmaceutical container comprising a container opening; moving at
least one of the fill needle and the at least one container to
dispose the fill needle over the container opening; dispensing the
pharmaceutical fluid through the dispensing tip and the container
opening into the at least one container; halting the dispensing to
retain within the fill needle a terminal pharmaceutical fluid
portion; and automatically removing the terminal pharmaceutical
fluid portion from the fill needle into the container after halting
the dispensing. The method may further comprise providing a
controller. The removing may be automatically initiated and
terminated by the controller.
[0030] Automatically removing the terminal pharmaceutical fluid
portion may comprise injecting an aseptic gas into the fill needle
tubing. Providing the fill needle may comprise providing a fill
needle having a gas inlet orifice in the fill needle tubing
proximate the dispensing tip; and injecting the aseptic gas into
the fill needle tubing may comprise injecting the aseptic gas via
the orifice. Injecting an aseptic gas into the fill needle tubing
may comprise injecting at least one of aseptic nitrogen gas,
aseptic air and aseptic helium gas. Injecting an aseptic gas into
the fill needle tubing may comprise filtering the gas to render it
aseptic. The method may comprise maintaining a flow of the gas
until no more pharmaceutical fluid is removed from the fill needle.
In another embodiment, automatically removing the terminal
pharmaceutical fluid portion may comprise inflating a bladder
within the dispensing tip.
[0031] Providing the fill needle may comprise providing a flexible
terminal tube disposed within the dispensing tip and a compression
actuator disposed to compress the flexible terminal tube; and
automatically removing the terminal pharmaceutical fluid portion
may comprise automatically operating the compression actuator to
compress the flexible terminal tube. Operating the actuator may
comprise piezoelectrically actuating the actuator or
electromechanically actuating the actuator.
[0032] Providing the fill needle may comprise providing the fill
needle tubing with a vibration actuator disposed on the fill needle
tubing for shaking the dispensing tip; and automatically removing
the terminal pharmaceutical fluid portion may comprise
automatically operating the vibration actuator to shake the
dispensing tip. Providing the fill needle may comprise providing a
fill needle having a gas channel surrounding the fill needle
tubing, the gas channel having an annular opening with respect to
and proximate to the dispensing tip; and wherein automatically
removing the terminal pharmaceutical fluid portion may comprise
blowing an aseptic gas at the terminal pharmaceutical fluid
portion. Providing the fill needle may comprise providing a fill
needle having a gas channel, the gas channel having an annular
opening with respect to and proximate the dispensing tip; and
wherein automatically removing the terminal pharmaceutical fluid
portion may comprise blowing an aseptic gas at the terminal
pharmaceutical fluid portion through the annular opening.
[0033] Providing a fill needle may comprise providing a first
robotic arm having a first end effector; and moving the fill needle
may comprise engaging the fill needle with the first end effector
and operating the robotic arm. Providing a first robotic arm may
comprise providing a first articulated robotic arm. Providing the
at least one container may comprise providing a container nest
bearing the at least one container. Providing the container nest
may further comprise providing a second robotic arm having a second
end effector; and moving the at least one container may comprise
engaging the container nest with the second end effector and
operating the second robotic arm. Providing the second robotic arm
may comprise providing a second articulated robotic arm. In another
embodiment, providing the container nest may comprise providing the
container nest held in a locating structure of a rotary stage, and
moving the at least one container may comprise rotating the rotary
stage.
[0034] Providing the fill needle may comprise providing the fill
needle closed with a fill needle sheath; sterilizing the chamber to
establish within the chamber an aseptic condition; and disengaging
and removing the fill needle from the fill needle sheath. The
method may further comprise engaging the fill needle with the fill
needle sheath after removing the terminal pharmaceutical fluid
portion from the fill needle.
[0035] In a further aspect, a fill needle system is presented for
aseptically dispensing a pharmaceutical fluid in a chamber capable
of maintaining an aseptic condition, the system comprising: a fill
needle hub, a fill needle tubing in fluid communication with a
pharmaceutical fluid source and extending through the fill needle
hub; a fill needle dispensing tip disposed at a dispensing end of
the fill needle tubing; a fill needle sheath shaped and arranged to
removably mate with and seal aseptically to the fill needle hub to
form an aseptically sealed volume enclosing the dispensing tip; and
a terminal fluid ejector disposed and configured for removing a
terminal pharmaceutical fluid portion from the dispensing tip.
[0036] The terminal fluid ejector may comprise a gas channel in
fluid communication with the dispensing tip via an orifice located
in the fill needle tubing fluidwise immediately upstream from the
dispensing tip. The system may further comprise a gas source for
supplying aseptic gas to the gas channel. The system may further
comprise a gas filter disposed to filter the gas from the gas
source in order to supply aseptic gas to the gas channel.
[0037] In another embodiment, the terminal fluid ejector may
comprise a bladder disposed and arranged to remove the terminal
pharmaceutical fluid portion from the dispensing tip when expanded
under the action of gas pressure. In another embodiment the
terminal fluid ejector may comprise a flexible terminal tube and an
electromechanical actuator or piezoelectric actuator that is
disposed and arranged to compress the flexible terminal tube.
[0038] In further embodiments, the terminal fluid ejector may
comprise a gas channel surrounding the fill needle tubing, the gas
channel having an annular opening with respect to and proximate to
the dispensing tip disposed to direct gas via the gas channel
toward the dispensing tip. In yet further embodiments, terminal
fluid ejector may comprise a vibration actuator disposed on the
fill needle tubing and arranged for shaking the dispensing tip.
[0039] The system may further comprise a controller configured to
control the dispensing of the pharmaceutical fluid via the
dispensing tip. The controller may be configured to automatically
operate the terminal fluid ejector to remove the terminal
pharmaceutical fluid portion after halting the dispensing of the
pharmaceutical fluid.
[0040] In a further aspect, a method is provided for aseptically
filling a pharmaceutical container with a pharmaceutical fluid, the
method comprising: in a chamber capable of maintaining an aseptic
condition providing a fill needle system comprising a fill needle,
the fill needle comprising fill needle tubing in fluid
communication with a dispensing tip; establishing in the chamber an
aseptic condition; providing in the chamber at least one aseptic
pharmaceutical container comprising a container opening; moving at
least one of the fill needle and the at least one container to
dispose the fill needle over the container opening; dispensing the
pharmaceutical fluid via flexible tubing through the dispensing tip
and the container opening into the at least one container; halting
the dispensing to retain on the dispensing tip a pharmaceutical
fluid droplet; and inducing a pressure pulse in the fluid in the
fill needle tubing to dislodge the droplet from the dispensing tip
into the container.
[0041] Providing the fill needle system may comprise providing a
fluid pressure pulse induction system and flexible tubing in fluid
communication with the fill needle tubing and the dispensing tip,
and the fluid pressure pulse induction system may be disposed and
configured to compress the flexible tubing. Inducing the pressure
pulse in the fluid may comprise operating the fluid pressure pulse
induction system to compress the flexible tubing. Compressing the
flexible tubing may comprise annularly compressing the flexible
tubing.
[0042] The method may further comprise providing a controller
operably coupled to the fluid pressure pulse induction system for
controlling the inducing of a pressure pulse in the fluid in the
fill needle tubing. The dispensing and the inducing a pressure
pulse in the fluid in the fill needle tubing may be automatically
controlled by the controller.
[0043] The method may further comprise moving at least one of the
fill needle and the at least one container to dispose the fill
needle over the container opening. The method may further comprise
providing in the chamber a first robotic arm having a first end
effector, and moving the fill needle may comprise engaging the fill
needle with the first end effector and operating the robotic arm.
Providing a first robotic arm may comprise providing a first
articulated robotic arm. The providing the at least one container
may comprise providing the at least one container in a container
nest. The method may further comprise providing a second robotic
arm having a second end effector, wherein moving the at least one
container comprises engaging the container nest with the second end
effector and operating the second robotic arm. Providing a second
robotic arm may comprise providing a second articulated robotic
arm.
[0044] Providing the at least one container may comprise providing
the at least one container in a container nest held in a locating
structure of a rotary stage, and moving the at least one container
may comprise rotating the rotary stage.
[0045] Providing the fill needle may comprise: providing the fill
needle closed with a fill needle sheath; sterilizing the chamber to
establish within the chamber an aseptic condition; and disengaging
and removing the fill needle from the fill needle sheath. The
method may further comprise engaging the fill needle with the fill
needle sheath after dislodging the droplet from the dispensing
tip.
[0046] In a further aspect, a fill needle system for aseptically
dispensing a pharmaceutical fluid in an aseptic chamber comprises a
fill needle tubing in fluid communication with a pharmaceutical
fluid source via flexible tubing and extending through a fill
needle hub; a fill needle dispensing tip disposed at a dispensing
end of the fill needle tubing; a fill needle sheath shaped and
arranged to removably mate with and seal aseptically to the fill
needle hub to form an aseptically sealed volume enclosing the
dispensing tip; and a fluid pressure pulse induction system
disposed and configured to compress the flexible tubing in order to
dislodge droplets of pharmaceutical fluid retained on the
dispensing tip after halting dispensing of the fluid.
[0047] The system may comprise a controller configured to control
the dispensing of the pharmaceutical fluid via the dispensing tip.
The controller may be configured to operate the fluid pressure
pulse induction system to automatically compress the flexible
tubing after halting dispensing of the pharmaceutical fluid. The
controller may be configured to induce in the fill needle tubing a
pressure pulse of predetermined fluid amplitude and duration
selected to specifically dislodge only a single droplet of
pharmaceutical fluid retained on the dispensing tip after halting
dispensing of the pharmaceutical fluid.
[0048] The fluid pressure pulse induction system may be disposed
and configured to annularly compress the flexible tubing. The fluid
pressure pulse induction system may be piezoelectrically,
pneumatically, electromechanically, or magnetically actuated.
[0049] Other features, elements, steps, characteristics and
advantages of the present invention will become more apparent from
the following detailed description of preferred embodiments of the
present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0050] In the drawings, which are not necessarily drawn to scale,
like numerals may describe similar components in different views.
Like numerals having different letter suffixes may represent
different instances of similar components. The drawings illustrate
generally, by way of example, but not by way of limitation, various
embodiments discussed in the present document.
[0051] FIG. 1 shows an apparatus for the protecting and
unprotecting of a fluid path in a controlled environment
enclosure.
[0052] FIG. 2 shows detail of an end piece of an apparatus for the
protecting and unprotecting of a fluid path in a controlled
environment enclosure
[0053] FIG. 3 shows detail of a robotic arm forming part of an
apparatus for the protecting and unprotecting of a fluid path in a
controlled environment enclosure
[0054] FIG. 4 is a flow chart for the typical prior art method.
[0055] FIG. 5 shows a method flow chart of an aspect of the
invention.
[0056] FIG. 6 shows a method flow chart of another aspect of the
invention.
[0057] FIG. 7 shows a method flow chart of another aspect of the
invention.
[0058] FIG. 8 shows a method flow chart of another aspect of the
invention.
[0059] FIG. 9A and FIG. 9B show isometric and sectional views
respectively of a combination of a fill needle and a fill needle
sheath, while FIG. 9C shows the combination of a fill needle and a
fill needle sheath with a tamper-indicator.
[0060] FIG. 10 shows a swab, swab sheath, and swab sheath cap for
use with the sheath removal station of FIG. 12 and robotic arm end
piece of FIG. 11.
[0061] FIG. 11 shows a robotic arm end piece according to one
embodiment of the invention for use with for use with the sheath
removal station of FIG. 12 and the fill needle and fill needle
sheath of FIG. 9A and FIG. 9B.
[0062] FIG.12 shows a sheath removal station according to one
embodiment of the invention.
[0063] FIG. 13 shows the sheath removal station of FIG. 2 with a
swab package and fill needle package suspended on the sheath
removal station before use.
[0064] FIG. 14A shows the fill needle package of FIG. 9A and FIG.
9B held by the robotic arm end piece of FIG.11.
[0065] FIG. 14B shows the fill needle package of FIG. 9A and FIG.
9B as well as the swab package of FIG. 10 held by the robotic arm
end piece of FIG. 11.
[0066] FIG. 15 shows a flow chart of (a) method for transferring
within a controlled environment enclosure a fluid along a fluid
path to a destination within the controlled environment enclosure
and (b) a method for installing a fluid path in the controlled
environment enclosure.
[0067] FIG. 16 shows a flowchart of a method for uninstalling from
a controlled environment enclosure a fluid path comprising a fill
needle.
[0068] FIG. 17 shows a purgeable fill needle arranged to fit in the
kind of fill needle sheath presented in FIG. 9A, FIG. 9B, and FIG.
9C.
[0069] FIG. 18 shows another implementation of a purgeable fill
needle arranged to fit in the kind of fill needle sheath presented
in FIG. 9A, FIG. 9B, and FIG. 9C.
[0070] FIG. 19 shows another implementation of a purgeable fill
needle arranged to fit in the kind of fill needle sheath presented
in FIG. 9A, FIG. 9B, and FIG. 9C.
[0071] FIG. 20 shows an implementation of a purgeable fill needle
employing a compression actuator for removing fluid from a
dispensing tip of the needle.
[0072] FIG. 21 shows an implementation of a purgeable fill needle
employing annularly directed gas to blow droplets of fluid from a
dispensing tip of the needle.
[0073] FIG. 22 shows an implementation of a purgeable fill needle
employing a vibration actuator for shaking attached droplets of
fluid from a dispensing tip of the needle.
[0074] FIG. 23 is a drawing of a flow chart for a method of
aseptically filling a pharmaceutical container with a
pharmaceutical fluid in a chamber capable of maintaining an aseptic
condition.
[0075] FIG. 24 shows an implementation of a fill needle system
employing a fluid pulse induction system to dislodge droplets of
fluid from a dispensing tip of a fill needle.
[0076] FIG. 25 shows an implementation of a fluid pulse induction
system.
[0077] FIG. 26 is a drawing of a flow chart for another method of
aseptically filling a pharmaceutical container with a
pharmaceutical fluid in a chamber capable of maintaining an aseptic
condition.
DETAILED DESCRIPTION
[0078] FIG. 1 shows an embodiment of an apparatus for protecting
and unprotecting of fluid path 404 in controlled environment
enclosure 420. The term "fluid" as used herein denotes any liquid,
gas, liquid-gas mixtures and any mixture of solids in liquid that
has fluid attributes, such as flowability or having appreciable
fluidity at ambient temperature and pressure, including, without
limitation, a dispersion of a solid or solids in a liquid, an
emulsion, a slurry, a micro-emulsion, colloidal suspension, a
suspension, a suspension of liposomes, and a suspension of micelles
or the like. The term "fluid path" as used herein denotes any
single channel or multi channel tubing or other pathway or
structure, rigid or flexible, for transporting a fluid.
[0079] Fluid path 404 starts at container 401. The term "container"
as used herein denotes any vessel suitable to hold a fluid,
including without limitation any vial, syringe, ampoule, carpule,
bottle, flask, beaker, bag, well in multi-well plates, tub or tube.
Container 401 is fitted with air filter 402. Container 401 may be
equipped with optional sensors (not shown) to measure volume,
weight of fluid, or other parameters. In some embodiments there may
be multiple containers connected in parallel or in series with one
another. Along fluid path 404 there may be optional measuring
devices (not shown) that measure properties, including without
limitation any one or more of pressure, flow, temperature, density
and conductivity. Fluid path 404 may be fitted with filter element
403. Filter element 403 may be selected to be suitable for sterile
filtration of fluids.
[0080] In FIG. 1 fluid path 404 comprises flexible tubing 405 and
enters controlled environment enclosure 420 via a sealed opening
(not shown). The sealing may be, for example, via the use of a
suitable aseptically sealing flange (not shown), which may seal by
means of, for example without limitation, an aseptic tri-clamp.
Container 401 and air filter 402 may be located outside controlled
environment enclosure 420, as shown in FIG. 1. In other embodiments
of the invention container 401 and air filter 402 may be located
inside controlled environment enclosure 420. Fluid pulse induction
subsystem 406 may or may not be present within fluid path 404, and
will be described in detail later below at the hand of FIG.24.
[0081] Controlled environment enclosure 420 is equipped with inlet
filter 430, inlet valve 431, blower 432, outlet filter 433 and
outlet valve 434. The characteristics of blower 432, inlet filter
430 and outlet filter 433 are chosen to yield a controlled
environment inside controlled environment enclosure 420. As
understood by those skilled in the art, various other filter and
blower arrangements are possible to establish a controlled
environment inside controlled environment enclosure 420. A suitable
controlled environment may be obtained, for example without
limitation, by means of any one or more of turbulent airflow,
horizontal unidirectional airflow and vertical unidirectional
airflow.
[0082] The fluid from container 401 may be transferred through
fluid path 404 by a variety of one or more different mechanisms,
including without limitation peristaltic pump 410 as shown in FIG.
1, a difference in pressure between container 401 and controlled
environment enclosure 420, a difference in static height of
container 401 and the end of fluid path 404, a gear pump, a lobe
pump, a membrane pump, a piston pump, or a syringe pump. In FIG. 1,
pump 410 is shown disposed inside controlled environment enclosure
420. In other embodiments, pump 410 may be disposed outside
controlled environment enclosure 420.
[0083] Flexible tubing 405 of fluid path 404 may terminate with end
piece 414. A suitable end piece may be, for example without
limitation, a fill needle, a pipette dispensing system, a syringe
dispensing system, a valve dispensing system, quick connectors,
aseptic connectors, dispense tips and a needle for piercing of
elastomers. In FIG. 1 end piece 414 is selected to include a fill
needle.
[0084] End piece 414 may be manipulated inside controlled
environment enclosure 420 by mechanical means, for example, robotic
arm manipulation system 415. One suitable robotic arm manipulation
system 415 may be an articulated robotic arm. Suitable robotic arm
manipulation systems for mechanically manipulating end piece 414
include, but are not limited to, 6-axis robotic arms, Selective
Compliant Articulated Robot Arm (SCARA) systems, r-theta robots, or
combinations of linear actuators and rotary actuators.
[0085] Fluids are transferred along fluid path 404 to a
destination, which may be containers such as the tray with vials
411 located on pedestal 412 in FIG. 1. The destination may be
microwell plates for pharmaceutical products.
[0086] Fluid path 404 may be employed for a variety of purposes
including without limitation the filling of empty containers,
washing and rinsing of containers, adding fluid to containers with
a freeze dried powder, adding fluids to containers containing
excipients and/or active ingredients, adding medium to cells,
tissue or microbes, inoculating cells or microbes, adding substrate
to enzyme solutions or suspensions of immobilized enzymes, adding
gases such as argon or nitrogen to create an inert head space in
containers, adding gases such as nitrogen, air or carbon dioxide to
cells and removing fluids out of containers by suction. The term
"excipient" as used herein denotes an inert substance used as a
diluent or vehicle for a drug.
[0087] Fluid path 404 may in some applications be required for
aseptic transfer of fluids. In such a case fluid path 404 may be
pre-sterilized before installation in controlled environment
enclosure 420. The aseptic part of fluid path 404 may start with
container 401 or with filter 403. Installation of aseptic fluid
path 404 requires sealing of end piece 414.
[0088] FIG. 4 is a flowchart showing the prior art method for
installing a fluid path in a prior art controlled environment
enclosure. The prior art method requires the steps in sequence of
decontaminating [100] the prior art controlled environment
enclosure; transferring [110] the fluid path into the prior art
controlled environment enclosure; and installing [120] by hand the
fluid path in the prior art controlled environment enclosure,
before using [130] the fluid path for the purpose for which it is
intended.
[0089] In an aspect of the invention there is provided a method for
installing fluid path 404 in controlled environment enclosure 420.
Referring to the apparatus of FIG. 1 and the flow chart of FIG. 5,
the method comprises protecting [301] fluid path 404 against an
environment external to fluid path 404, introducing [302] fluid
path 404 into controlled environment enclosure 420, decontaminating
[303] controlled environment enclosure 420, and mechanically
unprotecting [304] fluid path 404. In its unprotected state fluid
path 404 may then be used for transporting [305] fluids to
destination 411, which fluids may be aseptic or sterile fluids.
Such transporting [305] of fluids may comprise filtering the fluid
in fluid path 404 using filter element 403 and the filtering may be
sterile filtering. The terms "sterile" and "aseptic" are used
interchangeably in this specification. The term "decontamination"
as used herein denotes a process for removing or inactivating
contamination, including without limitation viruses, bacteria,
spores, prions, molds, yeasts, proteins, pyrogens and endotoxins,
to acceptable levels. "Decontamination" as used herein includes
both sterilization (that is, the destruction of all microorganisms,
including bacterial spores to a probability of surviving organisms
of typically less than 1:10.sup.6) and disinfection (that is, the
destruction and removal of specific types of micro-organisms).
[0090] In FIG. 2 a suitable arrangement for mechanically
unprotecting [304] fluid path 404 is shown, comprising end piece
414 of fluid path 404 in the form of a fill needle, together with
fill needle sheath 503. Fill needle 414 comprises fill needle
tubing 501 and fill needle hub 502. Fill needle tubing 501 is in
fluid communication with fluid path 404 of FIG. 1 and is
aseptically joined to fluid path 404. When fluid path 404 is within
controlled environment enclosure 420, fill needle sheath 503 may be
stored in sheath removal station 413 of controlled environment
enclosure 420 shown in FIG. 1.
[0091] Fill needle hub 502 and fill needle tubing 501 may be glued
or welded together. In alternative embodiments fill needle hub 502
and fill needle tubing 501 may be made as one part out of solid
material. Fill needle sheath 503 may be manufactured using
materials with different thermal expansion coefficients to allow it
to slide on and off fill needle hub 502 after thermal expansion.
Alternatively, fill needle sheath 503 may be designed to have a
sliding fit on fill needle hub 502 using porous PTFE or a steam
permeable elastomeric material.
[0092] Protecting [301] fluid path 404 comprises sealingly placing
fill needle sheath 503 over fill needle 414 such that fill needle
sheath 503 seals with needle hub 502. Fill needle sheath 503 and
needle hub 502 may be equipped with one or multiple of tamper
evident features 504 that will provide evidence of breaking the
seal between needle hub 502 and fill needle sheath 503. Possible
tamper evident features 504 include but are not limited to heat
shrink bands, tape seals, breakable rings, tear-off connectors and
snap connect tear-off connectors. Unprotecting [304] fluid path 404
comprises removing fill needle sheath 503 from fill needle 414,
thereby exposing fill needle 414 to an environment within
controlled environment enclosure 420. When fill needle 414 is in
use within controlled environment enclosure 420, fill needle sheath
503 is stored in sheath removal station 413.
[0093] Mechanically unprotecting [304] fill needle 414 when it is
within controlled environment enclosure 420 may comprise using
robotic arm manipulation system 415 shown in FIG. 1. FIG. 3
illustrates part of robotic arm manipulation system 415 of FIG. 1,
wherein forearm 601 is connected to wrist 602, and wrist 602 is
connected to tool flange 603. End tool 604, shown in FIG. 3 as
being fork shaped, has a partially opened bore of such diameter
that end tool 604 may slide around a narrow tubular section of
needle hub 502 and end tool 604 may move upwards to establish a
precise locating fit to needle hub 502. For unprotecting [304] fill
needle 414, end tool 604 moves fill needle 414 with fill needle
sheath 503 and places fill needle 414 with fill needle sheath 503
in sheath removal station 413.
[0094] In one embodiment of the apparatus and method, sheath
removal station 413 heats fill needle sheath 503, which thereby
expands and releases its grip or seal to needle hub 502.
Practitioners in the field will appreciate that there are many
different procedures and methods by which fill needle sheath 503
may be removed from fill needle 414. End tool 604, through the
motion of robotic arm manipulation system 415, removes fill needle
414 from fill needle sheath 503. Fill needle sheath 503 may remain
in sheath removal station 413 while robotic arm manipulation system
415 moves fill needle 414 to the destination. In one embodiment of
the apparatus and method the destination shown is the tray with
vials 411 located on pedestal 412 in FIG. 1.
[0095] End tool 604 and needle hub 502 may have various different
other shapes allowing the use of various other closure systems such
as, for example without limitation, a plug, a cap with sliding fit
o-ring seal with minimal occluded surface area, a cap with membrane
peel-off seal, or a twist-off cap. As understood by those skilled
in the art, some closure systems are more suitable than other
closure systems for use with particular sterilization methods.
[0096] Materials of lesser permeability may be used in the
manufacture of flexible tubing 405, but this is not always an
option. Tubing permeability may also be reduced by adding
additional layers to the tubing. Example methods for establishing
such additional layers around flexible tubing 405 include, but are
not limited to, heat shrinking with non-permeable polymers such as
FEP, multilayer co-extrusion with non-permeable polymers, creating
a diffusion barrier by polymeric coating such as poly(p-xylylene),
encasing with layers of tape, and the fitting of a sleeve.
[0097] In a further aspect of the invention there is provided a
method for uninstalling fluid path 404 from controlled environment
enclosure 420. Referring to the apparatus of FIG. 1 and the flow
chart of FIG. 6, the method comprises mechanically protecting [306]
fluid path 404 within controlled environment enclosure 420 once the
use of fluid path 404 has been completed, decontaminating [303]
controlled environment enclosure 420, and removing [307] fluid path
404 from controlled environment enclosure 420. Mechanically
protecting [306] fill needle 414 may comprise using robotic arm
manipulation system 415 shown in FIG. 1.
[0098] Mechanically protecting [306] fill needle 414 within
controlled environment enclosure 420 may comprise using robotic arm
manipulation system 415 of FIG. 1. End tool 604 (See FIG. 3) of
robotic arm manipulation system 415 is used to move fill needle 414
to and place it in fill needle sheath 503, which is housed in
sheath removal station 413. Sheath removal station 413 heats fill
needle sheath 503 until fill needle sheath 503 may slide over fill
needle 414 to suitably seal to needle hub 502 after cooling, to
thereby protect [306] fill needle 414 within controlled environment
enclosure 420. Robotic arm manipulation system 415 may then further
move protected fluid path 404 as may be required.
[0099] In a further aspect of the invention, mechanically
unprotecting [304] and mechanically protecting [306] fill needle
414 using robotic arm manipulation system 415 may be done
automatically. For example, suitable controller 440 (see FIG. 1),
communicating control instructions with controlled environment
enclosure 420 via control line 450, may be programmed to
automatically unprotect [304] fill needle 414 using robotic arm
manipulation system 415 once decontaminating [303] controlled
environment enclosure 420 has been completed. Such automation
obviates human intervention in the step of mechanically
unprotecting [304] fill needle 414. In an embodiment of the method,
the step of decontaminating [303] controlled environment enclosure
420 may also be managed by controller 440. This allows the
remainder of the steps of installing fill needle 414, beyond the
step of introducing [302] fluid path 404 into controlled
environment enclosure 420, to be automated using controller 440,
including the use of the fill needle for the purpose for which it
is installed, and mechanically protecting [306] fill needle 414
after such use.
[0100] In a further aspect of the invention there is provided a
method for decontaminating controlled environment enclosure 420
having fluid path 404. The method comprises mechanically protecting
[306] fluid path 404 within the controlled environment enclosure by
sealingly placing fill needle sheath 503 over fill needle 414 such
that fill needle sheath 503 seals with needle hub 502;
decontaminating [303] controlled environment enclosure 420; and
opening [308] and closing [309] controlled environment enclosure
420. Opening [308] and closing [309] controlled environment
enclosure 420 may be done after decontaminating [303] controlled
environment enclosure 420, as may be the case when the fluid or the
materials at the destination 411 are dangerous. This is shown in
FIG. 7. Alternatively, opening [308] and closing [309] controlled
environment enclosure 420 may be done before decontaminating [303]
controlled environment enclosure 420. This is shown in FIG. 8, as
may be the case when the external environment holds potential of
contaminating the fluid or the materials at the destination 411.
Mechanically protecting [306] fill needle 414 may comprise using
robotic arm manipulation system 415 shown in FIG. 1, as already
described.
[0101] Protecting [306] fill needle 414 using robotic arm
manipulation system 415 may be done automatically via controller
440 (see FIG. 1). Controller 440 may be programmed for
automatically mechanically protecting [306] fill needle 414 using
robotic arm manipulation system 415, prior to opening [308] and
closing [309] the controlled environment enclosure 420. Opening
[308] and closing [309] controlled environment enclosure 420 may
likewise be automated via controller 440.
[0102] We have described thus far herein an embodiment of sheath
removal station 413 of FIG. 1 based on employing heat to secure or
release fill needle 414 from fill needle sheath 503. We now turn to
another embodiment of the subsystem comprising sheath removal
station 413', fill needle 414', fill needle sheath 503', and
robotic arm manipulation system 415 described at the hand of FIGS.
9A, 9B, 10 and 11. In this embodiment, we describe an alternative
sheath removal system and associated sheath removal station 413',
and provide more detail as regards fill needle 414', fill needle
sheath 503', and robotic arm manipulation system 415.
[0103] FIG. 9A and FIG. 9B provide isometric and sectional views
respectively of fill needle sheath 503' and fill needle 414'
combination 900 of this embodiment. The term "aseptically sealed
fill needle package" 900 will be used in the present specification
to describe this combination of mutually aseptically sealed fill
needle sheath 503' and fill needle 414'. While FIG. 9A provides
perspective, the simplicity of FIG. 9B allows more elements to be
clearly indicated and numbered. Fill needle sheath 503' comprises a
substantially cylindrical vessel portion 910 configured to receive
the dispensing end of fill needle 414', and two clamping members
930a and 930b attached to vessel portion 910 by spring loaded
members 920a and 920b respectively. In one embodiment, shown in
FIG. 9A and FIG. 9B, the spring loading is established by means of
the natural elastic flexibility of members 920a and 920b. To this
end, fill needle sheath 503' may be manufactured from a polymeric
material with suitable inherent elasticity and that is compatible
with aseptic systems requirements. Locating eyelets 950a and 950b
are disposed in clamping members 930a and 930b respectively.
Clamping members 930a and 930b further comprise clamping clips 960a
and 960b respectively disposed to engage with filling needle 414'
as described in more detail below.
[0104] Filling needle 414' may be configured in many different
ways. In the present non-limiting exemplary embodiment, fill needle
414' comprises fill needle tubing 501' and fill needle hub 502'.
Fill needle 414' comprises dispensing portion 506', being the
dispensing tip of fill needle 414'. Fill needle tubing 501' is in
fluid communication with fluid path 404 of FIG. 1 and is
aseptically joined to fluid path 404. Fill needle hub 502' mates
axially face-to-face with fill needle sheath 503' in an aseptic
pressure seal provided by elastically compressible O-ring 940. Fill
needle hub 502' further comprises locating ledges 508a' and 508b'
for engaging with clamping clips 960a and 960b of filling needle
414'. In manufacture, spring loaded members 920a and 920b are
fashioned to be spring loaded when clamping clips 960a and 960b are
engaged with locating ledge 508'. When filling needle 414' is
sheathed in fill needle sheath 503' with compressible O-ring 940
under suitable compression, clamping clips 960a and 960b are
engaged with locating ledge 508' and under a tension force
directing clips 960a and 960b towards each other. Under these
circumstances, the tension in fill needle sheath 503' is contained
in spring loaded members 920a and 920b. Other embodiments for
urging clips 960a and 960b towards each other when filling needle
414' is sheathed in fill needle sheath 503' are contemplated,
including embodiments in which discrete springs are employed to
render members 920a and 920b spring loaded.
[0105] Fill needle sheath 503' may be manufactured by injection
molding of a suitable polymeric material. In order to keep units
costs low it may specifically be injection molded as a single
monolithic unit. In the present specification the term "monolithic"
is employed to describe an object that is fashioned is a contiguous
whole from one piece of material without joints or seams, whether
by casting, molding, or deposition, or any other means. A single
mold in the art of injection molding generally produces a
monolithic product. The locking member portions of fill needle hub
502' and fill needle sheath 503' may in particular be integrally
molded. This includes in particular spring-loaded members 920a and
920b.
[0106] Fill needle hub 502' comprises two engagement clips 510a'
and 510b' for engaging with robotic arm end piece 1100 of FIG. 11.
The operation of these will be described below at the hand of FIG.
11. Engagement clips 510a' and 510b' are able to flex such that
their top ends may be deflected closer together while engagement
clips 510a' and 510b' may push back in reaction against whatever
bodies are pushing them together. To this end engagement clips
510a' and 510b' may be spring loaded. In the embodiment of fill
needle hub 502' shown in FIGS. 9A and 9B, engagement clips 510a'
and 510b' are flexible by virtue of being manufactured from an
elastic material such as, for example without limitation, a
suitable polymeric material compatible with aseptic handling
requirements. Engagement clips 510a' and 510b' are shaped to both
clip over robotic arm end piece 1100 of FIG. 11 and be deflected
toward each other by end piece 1100.
[0107] In the embodiment shown in FIG. 9A and FIG. 9B, fill needle
hub 502' is shown as comprising several interior substructures.
This approach allows the same mold to be employed for the
manufacture by injection molding of all fill needle hubs, while the
interior substructures are then adapted to differently sized fill
needle tubing 501'. This allows costs to be kept low. Other
arrangements of substructures are also contemplated, including
without limitation embodiments wherein the entire fill needle hub
502' is one monolithic entity fashioned by injection molding of a
suitable polymeric material compatible with aseptic requirements.
Based on the above, fill needle package 900 comprises first and
second sheath portions that together define a sealed cavity that
aseptically encapsulates an implement portion when first and second
locking mechanism portions are mutually mated.
[0108] In view of the above, flow path 404 of FIG. 1, as supplied
for use in this embodiment, comprises flexible tubing 405, an
aseptically sealing flange for aseptically sealing flow path 404 to
controlled environment chamber 420, and aseptically sealed fill
needle package 900.
[0109] Turning now to FIG. 9C, aseptically sealed fill needle
package 900 may have tamper indicator 970 that is mechanically
linked to one of the locking mechanism portions of fill needle
package 900. In FIG. 9C tamper indicator 970 comprises a tearable
strip across spring loaded members 920a and 920b. When locating
eyelets 950a and 950b are forced apart, the portion of tamper
indicator 970 disposed across spring loaded members 920a and 920b
is torn irreversibly. Since the same act of separating locating
eyelets 950a and 950b also leads to the separation of sealing
surfaces between fill needle hub 502' and fill needle sheath 503',
the breaking of tamper indicator 970 is a direct indicator of the
breach of the aseptic seal between fill needle hub 502' and fill
needle sheath 503'. The same tamper-evident arrangement may be made
for the swab system described below.
[0110] As part of the process of filling a pharmaceutical container
with a pharmaceutical product, a regulatory requirement may exist
in some cases for the dispensing tip of fill needle 414, 414' to be
swabbed with a suitable swab to collect potential contamination
species. Such swabs are then typically evaluated by a suitably
qualified laboratory in order to assess the aseptic state of the
pharmaceutical dispensing process. To this end, in another aspect
of the invention, an aseptically sealable/unsealable swab subsystem
is provided. In FIG. 10, swab subsystem 1000 comprises swab holder
1003 that may usefully be of the same design as fill needle sheath
503' of FIG. 9A and FIG. 9B. Swab 1006 is mounted within swab
holder 1003 with collection tip 1008 of swab 1006 protruding above
the top of swab holder 1003. This arrangement allows the dispensing
tip of the fill needle 414, 414' to be swabbed by touching the
dispensing tip to collection tip 1008 of swab 1006. Swab holder
1003 may be a monolithic injection molded polymeric swab
holder.
[0111] Swab subsystem 1000 further comprises swab holder cap 1002
that may usefully be of the same design as fill needle hub 502' of
FIG. 9A and FIG. 9B, with this modification that swab holder cap
1002 has no fill needle tube 502' and that swab holder cap 1002 is
instead permanently sealed at the top. As regards all other
mechanical operational aspects, fill needle sheath 503' and fill
needle 414' combination 900 and swab subsystem 1000 may be
identical. For this reason, the mechanical design aspects of swab
subsystem 1000 will not be further discussed here. We shall,
however, be referring below to engagement clips 1010a' and 1010b'
of swab holder cap 1002 as regards their engagement with robotic
arm end piece 1100 of FIG. 11. We shall also be referring below to
locating eyelets 1050a and 1050b disposed in clamping members 1030a
and 1030b respectively as regards their engagement with fingers.
The term "aseptically sealed swab package" 1000 will be used in the
present specification to describe this combination of mutually
aseptically sealed swab holder cap 1002 and swab holder 1003
containing swab 1006. Swab 1006 is supplied for use packaged in the
form of aseptically sealed swab package 1000. Based on the above,
swab package 1000 comprises first and second sheath /portions that
together define a sealed cavity that aseptically encapsulates an
implement portion when first and second locking mechanism portions
are mutually mated. The locking member portions of swab holder cap
1002 and swab holder 1003 may in particular be integrally molded.
This includes in particular spring-loaded members of the
structure.
[0112] FIG. 11 shows one embodiment of endpiece 1100 for robotic
arm 415 of FIG. 1 configured to engage with swab subsystem 1000 of
FIG. 10 and with fill needle sheath 503' and fill needle 414'
combination 900 of FIG. 9A and FIG. 9B. Flange 1110 is disposed and
shaped for attaching endpiece 1100 to robotic arm 415 of FIG. 1.
Openings 1120 and 1140 are disposed and shaped for holding fill
needle 414' and swab holder cap 1004 respectively. In the case of
fill needle 414', engagement clips 510a' and 510b' of fill needle
hub 502' engage with end piece engagement surfaces 1120a and 1120b
of endpiece 1100.
[0113] Procedurally, fill needle 414' is engaged as follows with
endpiece 1100. Endpiece 1100 is moved forward over the part of fill
needle tubing 501' that protrudes out of fill needle 414' and any
associated section of flow path 404 joined to fill needle tubing
501' until opening 1120 is directly above fill needle 414'. In this
process, opening 1120c allows endpiece 1100 to negotiate fill
needle tubing 501'. Endpiece 1100 may then be lowered such that the
bottom edges of engagement surfaces 1120a and 1120b engage with the
sloped portions of engagement clips 510a' and 510b'. When endpiece
1100 is lowered further, engagement clips 510a' and 510b' are both
flexibly deflected towards each other until engagement surfaces
1120a and 1120b pass the sloped portions of engagement clips 510a'
and 510b' and engagement clips 510a' and 510b' snap back to engage
their flat surfaces with engagement surfaces 1120a and 1120b of
endpiece 1100. This securely locates fill needle 414' in endpiece
1100. When fill needle 414' is engaged with endpiece 1100, clamping
members 930a and 930b are disposed in slots 1130a and 1130b
respectively so as to render locating eyelets 950a and 950b
accessible.
[0114] In the case of swab holder cap 1004, the engagement proceeds
in the same fashion, except that there is no fill needle tubing
501' requiring an opening similar to 1120c. Endpiece 1100 is simply
moved until opening 1140 is directly above swab holder cap 1004,
after which endpiece 1100 is lowered such that the flat surfaces of
engagement clips 1010a' and 1010b' engage with surfaces 1140a and
1140b of opening 1140 in a fashion similar to that described above
for engagement clips 510a' and 510b'. When swab holder cap 1004 is
engaged with endpiece 1100, clamping members 1030a and 1030b are
disposed in slots 1150a and 1150b respectively so as to render
locating eyelets 1050a and 1050b accessible.
[0115] When first using fill needle 414, 414' and flow path 404,
the product to be dispensed into containers is first run through
flow path 404 and fill needle 414, 414' to establish a steady and
reliable flow. This initial volume of product may be dispensed into
a priming bottle to be disposed of later. Grip 1160 on endpiece
1100 may be employed as a general tool for handling, for example,
stoppers for such priming bottles and the like.
[0116] To describe the removal of fill needle sheath 503' from fill
needle 414', we turn now to FIG. 12, in which sheath removal
station 413' comprises sheath engagement fingers 1220a and 1220b
for engaging with locating eyelets 950a and 950b of fill needle
sheath 503'. When fill needle sheath 503', either with or without
fill needle 414' engaged with it, is forced onto sheath engagement
fingers 1220a and 1220b, the angled mutual orientation of sheath
engagement fingers 1220a and 1220b forces apart clamping members
930a and 930b of fill needle sheath 503'. This action forces
clamping clips 960a and 960b apart and disengages clamping clips
960a and 960b from locating ledge 508' of fill needle hub 502'.
O-ring 940 thereby is allowed to expand to its uncompressed state
and fill needle 414' is released from fill needle sheath 503'. Fill
needle sheath 503' is therefore removably sealable to fill needle
414'. When not in use, fill needle sheath 503' is aseptically
sealed to fill needle 414' and may be suspended from suspension
stubs 1240a and 1240b as shown in FIG. 13. As will be described
later, an operator may install flow path 404 in chamber 420. In
that process, fill needle sheath 503' with fill needle 414'
aseptically sealed to it, is positioned on suspension stubs 1240a
and 1240b.
[0117] Sheath removal station 413' also comprises sheath engagement
fingers 1230a and 1230b for engaging with locating eyelets 1050a
and 1050b of swab holder 1003. When swab holder 1003, either with
or without swab holder cap 1002 engaged with it, is forced onto
sheath engagement fingers 1230a and 1230b, the angled mutual
orientation of sheath engagement fingers 1230a and 1230b forces
apart clamping members 1030a and 1030b of swab holder 1003. This
action disengages swab holder cap 1002 from swab holder 1003. Swab
holder 1003 is therefore removably sealable to swab holder cap
1002. When not in use, swab holder 1003 aseptically sealed to swab
holder cap 1002 may be suspended from suspension stubs 1250a and
1250b as shown in FIG. 13. As will be described later, at the start
of the process of filling pharmaceutical containers with
pharmaceuticals in chamber 420, an operator may install swab holder
1003 aseptically sealed to swab holder cap 1002 on suspension stubs
1250a and 1250b as per FIG. 13.
[0118] FIG. 14A shows robotic arm endpiece 1100 holding aseptically
sealed fill needle package 900 by engagement clips 510a' and 510b'
of fill needle hub 502'. FIG. 14B shows robotic arm endpiece 1100
holding aseptically sealed swab package 1000 by engagement clips
1010a and 1010b of swab cap 1002.
[0119] In operation, fluid path 404 is sealed aseptically to
controlled environment enclosure 420 and fill needle package 900 is
suspended on suspension stubs 1240a and 1240b of sheath removal
station 413' as shown in FIG. 13. Swab package 1000 is introduced
into enclosure 420 and suspended on stubs 1250a and 1250b of sheath
removal station 413' as shown in FIG. 13. Controlled environment
enclosure 420 may now be decontaminated using any of the various
means previously described. Fluid path may now be unprotected by
unsealing fill needle 414' fill needle sheath 503'. This may be
done using robotic arm 415 as explained above at the hand of FIG.
12. This step leaves fill needle sheath 503' located on sheath
engagement fingers 1220a and 1220b and fill needle 414' located on
robotic arm endpiece 1100.
[0120] Swab holder cap 1002 may be similarly removed from swab
holder 1003 to expose swab 1006 to the environment in enclosure
420. The process leaves swab holder 1003 with swab 2006 located on
sheath engagement fingers 1230a and 1230b of sheath removal station
413'. Robotic arm 415 now may proceed to fill pharmaceutical vials
411 located on pedestal 412 in FIG. 1 with fluid via fill needle
414'. Fill needle 414' and swab holder cap 1002 remain resident on
robotic arm endpiece 1100 during the filling process.
[0121] When filling has been completed, robotic arm 415
automatically moves robotic arm endpiece 1100 with fill needle 414'
and swab holder cap 1002 to sheath removal station 413' to touch
dispensing end 506' of fill needle 414' to exposed tip 1008 of swab
1006.
[0122] Using robotic arm 415, eyelets 950a and 950b of fill needle
sheath 503' are engaged with sheath engagement fingers 1220a and
1220b to allow fill needle 414' to be aseptically sealed to fill
needle sheath 503', thereby protecting the fluid path 404. Eyelets
1050a and 1050b of swab holder 1003 may similarly engage with
sheath engagement fingers 1230a and 1230b of sheath removal station
413' to alllow swab holder 1003 and swab holder cap 1002 to be
sealed aseptically to each other, thereby protecting swab 2006.
Fluid path 404 and sealed swab package 1000 may now be removed from
controlled environment enclosure 420.
[0123] As shown in FIG. 14B, robotic arm endpiece 1100 has no
moving parts and is capable of simultaneously bearing both fill
needle package 900 and swab package 1000. Despite both robotic arm
endpiece 1100 and sheath removal station 413' having no moving
parts, they are jointly capable of opening and closing both fill
needle package 900 and swab package 1000. This is possible by
virtue of the interaction between the engagement fingers 1220a,
1220b, 1230a, 1230b of sheath removal station 413' and eyelets 950a
and 950b of fill needle sheath 503' and eyelets 1050a and 1050b of
swab holder 1003, combined with the spring-loaded or flexible
nature of portions of fill needle sheath 503' and swab holder
1003.
[0124] In one aspect of the invention, described at the hand of
FIG. 15, a method is provided for transferring [1500] within a
controlled environment enclosure a fluid along a fluid path to a
destination within the controlled environment enclosure, the method
comprising providing [1510] an aseptically sealed fluid path
comprising an aseptically sealed fill needle package, aseptically
sealing [1520] the fluid path to the controlled environment
enclosure, decontaminating [1530] the controlled environment
enclosure after aseptically sealing the fluid path to the
controlled environment enclosure, automatically unprotecting [1540]
the fluid path within the controlled environment enclosure,
transferring [1550] the fluid to the destination along the fluid
path after the automatically unprotecting, and disposing without
re-using [1570] of the fluid path after transferring the fluid to
the destination.
[0125] The automatically unprotecting [1540] may be by
automatically operating a robotic arm. The decontaminating [1530]
the controlled environment enclosure may automatically be done
after the sealing the fluid path to the controlled environment
enclosure. The providing an aseptically sealed fluid path [1510]
may comprise providing a fill needle removably and aseptically
sealed to a fill needle sheath and the sheath may be a monolithic
injection molded polymeric fill needle sheath. Providing an
aseptically sealed fluid path [1510] may comprise providing a
pre-sterilized tube aseptically sealed to the fill needle.
Transferring [1550] the fluid to a destination may comprise
transferring the fluid to at least one of a culture of cells, a
culture of tissue, an enzyme solution, a suspension of immobilized
enzymes, a mix of active ingredients, and an excipient.
Transferring [1550] the fluid may be transferring an aseptic fluid.
Transferring [1550] within a controlled environment enclosure may
be transferring within an isolator. The transferring the fluid
[1550] to a destination may comprise at least one of transferring
the fluid to microwell plates and to containers for pharmaceutical
products.
[0126] The method may further comprise automatically protecting
[1560] the fluid path after transferring the fluid to the
destination and before disposing of the fluid path. Transferring
[1550] the fluid may comprise filtering the fluid in the fluid
path. The filtering may be sterile filtering.
[0127] As part of the method described above, a method [1500a ] is
provided for installing a fluid path within a controlled
environment enclosure comprising, providing [1510] an aseptically
sealed fluid path comprising an aseptically sealed fill needle
package, aseptically sealing [1520] the fluid path to the
controlled environment enclosure, decontaminating [1530] the
controlled environment enclosure after aseptically sealing the
fluid path to the controlled environment enclosure, and
automatically unprotecting [1540] the fluid path within the
controlled environment enclosure. The automatically unprotecting
may be by automatically operating a robotic arm. The
decontaminating the controlled environment enclosure may be
automatically done after the sealing the fluid path to the
controlled environment enclosure. The providing a fill needle may
comprise providing a fill needle removably and aseptically sealed
to a fill needle sheath. The providing a fill needle may comprise
providing a fill needle removably and aseptically sealed to a
monolithic injection molded polymeric fill needle sheath.
[0128] In a further aspect of the invention described at the hand
of FIG. 16, a method is provided for uninstalling [1600] from a
controlled environment enclosure a fluid path comprising a fill
needle, the method comprising automatically aseptically sealing
[1610] the fill needle to a monolithic injection molded polymeric
fill needle sheath within the controlled environment enclosure,
decontaminating [1640] the controlled environment enclosure after
aseptically sealing [1610] the fluid path, opening [1650] the
controlled environment enclosure after the decontaminating [1640],
and removing [1660] the fluid path from the controlled environment
enclosure. The method may further comprise automatically swabbing
[1620] a dispensing end of the fill needle with a swab and
automatically aseptically sealing the swab [1630] in a swab package
before decontaminating [1640] the controlled environment, and
removing [1670] the swab package from the controlled environment
enclosure after opening the controlled environment enclosure.
[0129] Automatically aseptically sealing the fluid path [1610] may
be by automatically operating a robotic arm. Decontaminating [1640]
the controlled environment enclosure may be done automatically
after sealing [1610] the fluid path. Opening [1650] the controlled
environment enclosure is done automatically after decontaminating
[1640] the controlled environment enclosure. Automatically swabbing
[1620] may be by automatically operating a robotic arm.
Automatically aseptically sealing [1610]
[0130] the fluid path may be by automatically operating the robotic
arm. Decontaminating [1640 ] the controlled environment enclosure
may be done automatically after sealing the fluid path [1610] and
sealing the swab [1630]. Swabbing [1620] may be with a swab
disposed in a monolithic injection molded polymeric swab
holder.
[0131] As part of the above methods, a subsidiary method is
provided for decontaminating a controlled environment enclosure
containing a fluid path having a fill needle, the method comprising
automatically aseptically sealing [1610] the fill needle to a
monolithic injection molded polymeric fill needle sheath within the
controlled environment enclosure, and decontaminating [1620] the
controlled environment enclosure after aseptically sealing [1610]
the fluid path. Automatically aseptically sealing [1610] the fluid
path may be by automatically operating a robotic arm. A subsidiary
method is also provided for decontaminating a controlled
environment enclosure containing a swab disposed in a swab holder,
the method comprising automatically aseptically sealing the swab
holder to a swab holder cap [1630] within the controlled
environment enclosure, and decontaminating [1640] the controlled
environment enclosure after aseptically sealing the swab holder to
a swab holder cap. Automatically aseptically sealing [1630] the
swab holder to a swab holder cap may be by automatically operating
a robotic arm.
[0132] In the above-described embodiments, a pair of
injection-molded parts are snapped together using integrally molded
leaf spring members with clamping clips that engage with locating
ledges. This action provides a positive mechanical detent that
ensures that the implement is reliably sealed inside the sheath.
But one of ordinary skill in the art would recognize that a variety
of other types of mechanisms may be used to provide this type of
action, including but not limited to cam-based mechanisms,
ratcheting mechanisms, bistable linkages, spring-loaded balls,
snaps, and latch pins.
[0133] The mechanisms in the above-described embodiments are
presented in configurations that allow a concave sheath and
cover-like hub to be engaged with each other along a vertical axis,
but other geometric configurations may also be implemented. A pair
of concave sheath portions could both partly enclose an implement
in a downward-facing clamshell-type configuration, for example. And
while the sheath and its corresponding hub are preferably
manufactured as two completely separate parts as described above,
they could also be built as a compound unit, such as by connecting
them with a hinge or tether.
[0134] The above-described embodiments also provide bearing
surfaces on engagement clips and in eyelets that respectively
interact with an endpiece on a robot arm and protrusions on a
holding station, which allow a robot arm to automatically open and
close the sheath. But one of ordinary skill in the art would
recognize that many other combinations and arrangements of bearing
surfaces could also be employed.
[0135] In another aspect, a fill needle arrangement shown in FIG.
17 is provided for aseptically dispensing, along fluid path 404 of
FIG. 1, pharmaceutical fluid 702 into pharmaceutical container 411
within chamber 420, chamber 420 being capable of maintaining an
aseptic condition. In describing the method and associated system,
we shall refer to components and subsystems shown in FIG. 1, though
the method may apply to other dispensing systems, including the
rotary stage filling systems described in co-pending United States
Patent Publications US 2018-0072446 A1 (published Mar. 15, 2018),
US 2018-0071168 A1 (published Mar. 5, 2018), and US 2018-0282008 A1
(published Oct. 4, 2018), and PCT International Patent Publication
WO/2018/049516 (published Mar. 22, 2018), the disclosures of which
are hereby incorporated by reference in their entirety.
Furthermore, while FIG. 1 shows peristaltic pump 410 as located
within aseptic chamber 420, peristaltic pump 410 may be located
outside aseptic chamber 420 in order to reduce contamination by
moving parts and to limit the extent of locations where biological
species may find harbor during sterilization of chamber 420. In
describing the method and associated system, we shall refer to fill
needle and fill needle sheath arrangements shown in FIGS. 9A, 9B
and 9C, though the method may apply to other implementations of
fill needles and fill needle sheaths.
[0136] FIG. 17 shows an implementation of a purgeable fill needle
employing fill needle hub 502a of the same general arrangement as
fill needle hub 502' described above at the hand of FIGS. 9A, 9B
and 9C, fill needle hub 502a shaped and arranged to mate with a
fill needle sheath (not shown in FIG. 17) of the same general
arrangement as that of sheath 503' of FIGS. 9A, 9B and 9C. In this
implementation, fill needle tubing 501a is provided with gas inlet
orifice 509A via which gas may be injected into needle tubing 501a
proximate dispensing tip 506a. Gas may be provided through gas tube
507a via gas line 464 from a gas source that may be located outside
chamber 420. Needle tubing 501a and gas tube 507a are arranged
within fill needle hub 502a such that the combination mates with
and fits into a sheath of the same type as sheath 503' in FIGS. 9A,
9B and 9C. Gas line 464 and flexible tubing (see also FIG.1) are
joined to respectively gas tube 507a and fill needle tubing 501a by
connector 505a, shown schematically in FIG. 17. As already
described, flexible tubing 405 enters chamber 420 (See FIG. 1) via
a suitable aseptically sealing flange, so that the exterior of
fluid path 404 within chamber 420 is aseptically sealed to the
interior of chamber 420. Gas line 464 enters chamber 420 via a
suitable aseptically sealing flange (not shown), so that the
exterior of gas line 464 within chamber 420 is aseptically sealed
to the interior of chamber 420.
[0137] At least interior 512a of the terminal region of dispensing
tip 506a between the end of fill needle tubing 501a and gas inlet
orifice 509A may be at least one of lined with a hydrophobic
material, coated with a hydrophobic material, and treated to render
it hydrophobic, or may consist of a separate section of hydrophobic
tubing. This lowers the ability of water-based or other polar
pharmaceutical fluids to stick to the inside wall of dispensing tip
506a. The lowered attraction of such fluids to the interior wall of
dispensing tip 506a facilitates the purging of fluid from
dispensing tip 506a. The term "hydrophobic" is used in the present
specification as being synonymous with "low surface energy".
[0138] In operation, when the flow of pharmaceutical fluid through
fill needle tubing 501a is halted, an amount of pharmaceutical,
shown as 704a in FIG. 17 and referred to in this specification as
the "terminal pharmaceutical fluid portion", remains in or attached
to dispensing tip 506a. This may be in the form of fluid between
the end of fill needle tubing Ola and gas inlet orifice 509A and/or
a droplet of pharmaceutical fluid that has remained attached to the
fill needle tip. The inventors have found empirically that the
action of removing terminal pharmaceutical fluid 704a retained in
the proximity of the dispensing end of dispensing tip 506a results
in distinctly more repeatable dispensing volumes.
[0139] In the fill needle arrangement of FIG. 17, halting of the
flow of pharmaceutical fluid via fluid path 404 (represented by
tubing portion 405 in FIG. 17) may be followed by injection of a
suitable aseptic gas, for example without limitation air or
nitrogen, into fill needle tubing 501a via gas tube 507a and gas
line 464 to form gas pocket 706a. As the gas flow continues and gas
pocket 706a expands toward the end of dispensing tip 506a, terminal
fluid 704a is removing from dispensing tip 506a. Removed terminal
fluid 704a may be released from the end of dispensing tip 506a in
the form of droplets, for example droplet 708a. The gas flow may be
turned on and off automatically by means of suitable valve 466
under control of a controller, for example controller 440 of FIG.
1. To this end, valve 466 may be in communication with controller
440 via valve control line 452. The term "terminal fluid ejector"
is used in the present specification to describe the arrangement
for removing the terminal pharmaceutical fluid portion 704a. Filter
468 in gas line 464 may be employed to filter the gas supplied to
gas tube 507a.
[0140] The fill needle may be positioned by a robotic arm, which
may be an articulated robotic arm of the type shown as articulated
robotic arm 415 in FIG. 1. Robotic arm 415 may have an end
effector, for example end effector 1100 of FIG.11, to engage fill
needle hub 502', as shown in FIG. 14A. In FIG. 1 the containers 411
are shown as positioned in a tray on pedestal 412. In other
embodiments, the containers may be held in a nest and the nest
moved by a robotic arm, the robotic arm in some embodiments being
an articulated robotic arm. A non-limiting example of such an
arrangement is provided in U.S. patent application Ser. No.
15,729,655 in which FIG. 9 of that application shows containers 510
in a nest 500 and nest 500 is moved by an articulated robotic arm
800. Either or both of the container and the fill needle may be
moved to ensure that the fill needle dispensing tip 506a is
positioned over the container.
[0141] FIG. 18 shows another embodiment of a purgeable fill needle
employing fill needle hub 502b of the same general arrangement as
fill needle hub 502' described above at the hand of FIGS. 9A, 9B
and 9C, fill needle hub 502b shaped and arranged to mate with a
fill needle sheath (not shown in FIG. 18) of the same general
arrangement as that of sheath 503' of FIGS. 9A, 9B and 9C. It
differs from the embodiment shown in FIG. 17 in that the gas is
channeled along annular sheath 507b around fill needle tubing 501b.
The term "gas channel" is used in the present specification to
describe both annular sheath 507b of FIG. 18 and gas tube 507a of
FIG. 17. The gas then enters fill needle tubing 501b at gas inlet
orifice 509B to form gas pocket 706b. As in the embodiment of FIG.
17, terminal pharmaceutical fluid portion 704b is forced out of
dispensing tip 506b in the form of droplets, for example droplet
708b. At least interior 512b of the terminal region of dispensing
tip 506b between the end of fill needle tubing 501b and gas inlet
orifice 509B may be at least one of lined with a hydrophobic
material, coated with a hydrophobic material, and treated to render
it hydrophobic, or may consist of a separate section of hydrophobic
tubing. As with the embodiment in FIG. 17, the term "terminal fluid
ejector" is used in the present specification to describe the
arrangement of elements for removing the terminal pharmaceutical
fluid portion 704b. Gas line 464 and flexible tubing 405 (See FIG.
1) are joined to respectively tube 507b and fill needle tubing 501b
by connector 505b, shown schematically in FIG. 18. Filter 468 in
gas line 464 may be employed to filter the gas supplied to annular
sheath 507b.
[0142] Whereas the fill needle implementations in both FIG. 17 and
FIG. 18 are configured for mating with sheaths of the type 503' in
FIGS. 9A, 9B and 9C, they may be employed with any other suitable
sheathing arrangement, including but not limited to that of FIG.
2.
[0143] FIG. 19 shows another embodiment of a purgeable fill needle
employing fill needle hub 502c of the same general arrangement as
fill needle hub 502' described above at the hand of FIGS. 9A, 9B
and 9C, fill needle hub 502c shaped and arranged to mate with a
fill needle sheath (not shown in FIG. 18) of the same general
arrangement as that of sheath 503' of FIGS. 9A, 9B and 9C.
Dispensing tip 506c is configured to produce droplets 708c of
pharmaceutical fluid 702. In this embodiment, dispensing tip 506c
comprises inflatable annular bladder 511, which may be
pneumatically inflated or deflated by controlling the gas pressure
in bladder 511. As in the embodiment of FIG. 18, the gas pressure
may be controlled by controller 440 via control line 453 to valve
467. Valve 467 may, for example, inflate bladder 511 by injecting
gas from gas line 462 via annular gas channel 507c and through gas
inlet orifice 509C. Conversely, valve 467 may, for example, deflate
bladder 511 by releasing gas from annular gas channel 507c. When
annular bladder 511 is inflated, terminal pharmaceutical fluid
portion 704c may be pneumatically removed from dispensing tip
506'c. As with the embodiment of FIG. 18, dispensing tip 506c may
be at least in part lined with a hydrophobic material, coated with
a hydrophobic material, or treated to render it hydrophobic. As
with the embodiments in FIG. 17 and FIG. 18, the term "terminal
fluid ejector" is used in the present specification to describe the
arrangement of elements for removing the terminal pharmaceutical
fluid portion 704c.
[0144] Gas line 462 and flexible tubing 405 (See also FIG. 1) are
joined to respectively annular gas channel 507c and fill needle
tubing 501c by connector 505c, shown schematically in FIG. 19. Gas
line 462 enters chamber 420 via a suitable aseptically sealing
flange (not shown), so that the exterior of gas channel 507c and
the exterior of the gas line 462 within chamber 420 are aseptically
sealed to the interior of chamber 420. In operation, the gas
employed in the embodiment of FIG. 19 does not come into direct
contact with the pharmaceutical fluid as long as the bellows retain
integrity, and is not subject to the same sterility requirements as
the gas employed in the embodiments of FIG. 17 and FIG. 18.
[0145] FIG. 20 shows another embodiment of a purgeable fill needle
employing fill needle hub 502d of the same general arrangement as
fill needle hub 502' described above at the hand of FIGS. 9A, 9B
and 9C, fill needle hub 502d shaped and arranged to mate with a
fill needle sheath (not shown in FIG. 18) of the same general
arrangement as that of sheath 503' of FIGS. 9A, 9B and 9C. Flexible
tubing 405 (see also FIG. 1) is joined to fill needle tubing 501d
by connector 505d, as shown schematically in FIG. 19. Dispensing
tip 506d is configured to produce droplets 708d of pharmaceutical
fluid 702. In this embodiment, dispensing tip 506d internally
comprises a flexible terminal tube 515 attached to fill needle
tubing 501d and compression actuator 513 configured for driving a
compression element 517 to compress flexible terminal tube 515 in
order to remove terminal pharmaceutical fluid portion 704d.
Controller 440 may control actuator 513 via control line 454.
Control line 454 may pass connectably through connector 505d. This
allows terminal pharmaceutical fluid portion 704d to be
automatically removed without direct operator intervention.
Flexible terminal tube 515 may be at least in part lined with a
hydrophobic material, coated with a hydrophobic material, or
treated to render it hydrophobic. Flexible terminal tube 515 may be
made from a hydrophobic material.
[0146] Several arrangements for actuator 513 may be implemented. In
one embodiment, compression actuator 513 may be piezoelectrically
driven. Levered piezoelectric actuators are capable of
displacements of the order of 1 millimeter which is sufficient
displacement for compression element 517 of actuator 513. In other
embodiments, actuator 513 may be electromechanically driven. In
both these embodiments, compression element 517 may be driven by a
suitable armature or lever structure (not shown) within actuator
513. Both kinds of actuators are well known in the art and are not
discussed here in more detail. As with the embodiments in FIG. 17,
FIG. 18, and FIG. 19, the term "terminal fluid ejector" is used in
the present specification to describe the arrangement of elements
for removing the terminal pharmaceutical fluid portion 704d.
[0147] FIGS. 21 and 22 show two implementations in which the
terminal pharmaceutical fluid portion is substantially composed of
a single droplet of pharmaceutical fluid that remains attached to
the dispensing tip of the fill needle after halting the dispensing
of fluid. FIG. 21 shows a variant of the embodiment presented in
FIG. 18 in which only the dispensing end of the fill needle differs
from that shown in FIG. 18. In FIG. 21 a purgeable fill needle
employs fill needle hub 502e of the same general arrangement as
fill needle hub 502' described above at the hand of FIGS. 9A, 9B
and 9C, fill needle hub 502e shaped and arranged to mate with a
fill needle sheath (not shown in FIG. 21) of the same general
arrangement as that of sheath 503' of FIGS. 9A, 9B and 9C. Gas is
channeled along annular sheath 507e around fill needle tubing 501e.
The term "gas channel" is used in the present specification to
describe annular sheath 507e. The gas then be directed across the
outlet of fill needle tubing 501e via annular gas outlet orifice
509B to blow the droplet forming terminal pharmaceutical fluid
portion 704e off dispensing tip 506e in the form of unattached
droplets, for example droplet 708e. At least interior 512e of the
terminal region of dispensing tip 506e may be lined with a
hydrophobic material, coated with a hydrophobic material, or
treated to render it hydrophobic, or may consist of a separate
section of hydrophobic tubing. The term "terminal fluid ejector" is
used in the present specification to describe the arrangement of
elements for removing the terminal pharmaceutical fluid portion
704e. Gas line 464 and flexible tubing 405 (See FIG. 1) are joined
to respectively tube 507e and fill needle tubing 501e by connector
505b, shown schematically in FIG. 21. Filter 468 in gas line 464
may be employed to filter the gas supplied to annular sheath
507e.
[0148] In another embodiment shown in FIG. 22 a purgeable fill
needle employs fill needle hub 502f of the same general arrangement
as fill needle hub 502' described above at the hand of FIGS. 9A, 9B
and 9C, fill needle hub 502f shaped and arranged to mate with a
fill needle sheath (not shown in FIG. 22) of the same general
arrangement as that of sheath 503' of FIGS. 9A, 9B and 9C. Actuator
519 is disposed to vibrate fill needle tubing 501e to remove from
dispensing tip 506f terminal pharmaceutical fluid portion 704f
which, in this case, is droplet 704f. This then produces
independent droplets, for example droplet 708f. At least interior
512f of the terminal region of dispensing tip 506f may be at least
one of lined with a hydrophobic material, coated with a hydrophobic
material, and treated to render it hydrophobic, or may consist of a
separate section of hydrophobic tubing. The term "terminal fluid
ejector" is used in the present specification to describe the
arrangement of elements for removing terminal pharmaceutical fluid
portion 704f. Controller 440 may control actuator 519 via control
line 455. This allows terminal pharmaceutical fluid portion 704f to
be automatically removed without direct operator intervention.
Actuator 519 may be actuated on any suitable basis, including
without limitation electromechanically and piezolectrically.
Flexible tubing 405 (See also FIG. 1) is joined to respectively
fill needle tubing 501e by connector 505f, shown schematically in
FIG. 21. Control line 455 may pass connectably through connector
505f.
[0149] In another aspect, described at the hand of the flow chart
shown in FIG. 23, a method is provided for aseptically filling
pharmaceutical container 411 with pharmaceutical fluid 702 using
the purgeable fill needle of FIG. 17, FIG. 18, FIG. 19, or FIG. 20,
the method comprising: in a chamber 420 (See FIG. 1) capable of
maintaining an aseptic condition providing [2310] a fill needle
comprising fill needle tubing 501a, 501b, 501c, 501d, 501e, 501f
having dispensing tip 506a, 506b, 506c, 506d, 506e, 506f ;
Establishing [2320] in the chamber 420 an aseptic condition;
providing [2330] in the chamber 420 at least one aseptic
pharmaceutical container 411 comprising a container opening; moving
[2340] at least one of the fill needle and the at least one
container to dispose the fill needle over the container opening;
dispensing [2350] pharmaceutical fluid 702 through dispensing tip
506a, 506b, 506c, 506d, 506e, 506f and the container opening into
the at least one container 411; halting [2360] dispensing to retain
within the fill needle a terminal pharmaceutical fluid portion
704a, 704b, 704c, 704d, 704e, 7046f; and automatically removing
[2370] terminal pharmaceutical fluid portion 704a, 704b, 704c,
704d, 704e, 704f from the fill needle into the container after
halting [2360] dispensing. The method may further comprise
providing a controller, for example controller 440 of FIG. 1.
Removing [2370] may be automatically initiated and terminated by
controller 440.
[0150] As per the systems of FIG. 17 and FIG. 18, automatically
removing terminal pharmaceutical fluid portion 704a, 704b may
comprise injecting aseptic gas into fill needle tubing 501a, 501b.
Providing the fill needle may comprise providing a fill needle
having gas inlet orifice 509A, 509B in fill needle tubing 501a,
501b proximate dispensing tip 506a, 506b ; and injecting aseptic
gas into fill needle tubing 501a, 501b may comprise injecting
aseptic gas via orifice 509A, 509B. The method may comprise
maintaining a flow of gas until no more pharmaceutical fluid 702 is
removed from the fill needle. In another embodiment, as per FIG.
19, automatically removing [2370] terminal pharmaceutical fluid
portion 704c may comprise inflating bladder 511 within dispensing
tip 506c.
[0151] Injecting aseptic gas may comprise injecting aseptic
nitrogen gas, aseptic air, or aseptic helium gas. Injecting aseptic
gas may comprise filtering gas to render it aseptic. Injecting
aseptic gas may comprise operating a gas valve, for example valve
466 of FIG. 17 and FIG. 18. Operating gas valve 466 may comprise
automatically controlling valve 466 by means of controller 440 of
FIG. 1 via valve control line 452.
[0152] Providing [2310] the fill needle may comprise, as per FIG.
20, providing flexible terminal tube 515 disposed within dispensing
tip 506d and compression actuator 513 disposed to compress flexible
terminal tube 515; and automatically removing [2370] terminal
pharmaceutical fluid portion 704d may comprise automatically
operating compression actuator 513 to compress flexible terminal
tube 515. Operating actuator 513 may comprise piezoelectrically
actuating the actuator or electromechanically actuating actuator
513.
[0153] Providing [2310] the fill needle may comprise providing the
fill needle tubing with a vibration actuator disposed on the fill
needle tubing for shaking the dispensing tip and automatically
removing [2370] the terminal pharmaceutical fluid portion comprises
automatically operating the vibration actuator to shake the
dispensing tip.
[0154] Providing [2310] the fill needle may comprise providing a
fill needle having a gas channel surrounding the fill needle
tubing, the gas channel having an annular opening with respect to
and proximate to the dispensing tip; and automatically removing
[2370] the terminal pharmaceutical fluid portion may comprise
annularly blowing an aseptic gas at the terminal pharmaceutical
fluid portion through the annular opening.
[0155] Providing [2310] the fill needle may comprise providing a
first robotic arm, for example robotic arm 415 of FIG. 1, having a
first end effector, for example end effector 1100 of FIG. 14B; and
moving the fill needle may comprise engaging the fill needle with
the first end effector 1100 and operating the robotic arm 415.
Providing a first robotic arm may comprise providing first
articulated robotic arm 415.
[0156] Providing [2330] at least one container 411 may comprise
providing a container nest bearing at least one container 411.
Providing the container nest may further comprise providing a
second robotic arm having a second end effector; and moving the at
least one container may comprises engaging the container nest with
the second end effector and operating the second robotic arm.
Providing the second robotic arm may comprise providing a second
articulated robotic arm. FIG. 9 of U.S. patent application Ser. No.
15,729,655, herein incorporated in full, shows containers 510 in a
nest 500 and nest 500 is moved by an articulated robotic arm 800,
which serves as second robotic arm in the present specification. In
another embodiment, providing the container nest may comprise
providing the container nest held in a locating structure of a
rotary stage, and moving the at least one container may comprise
rotating the rotary stage. Suitable rotary stages for holding and
moving nests of containers are described in detail in United States
Patent Publications US 2018-0072446 A1 (published Mar. 15, 2018),
US 2018-0071168 A1 (published Mar. 15, 2018), and US 2018-0282008
A1 (published Oct. 4, 2018), and PCT International Patent
Publication WO/2018/049516 (published Mar. 22, 2018), all of which
are herein incorporated in full.
[0157] Providing [2310] the fill needle may comprise providing the
fill needle closed with a fill needle sheath, for example fill
needle sheath, for example sheath 503' of FIG. 9A; sterilizing
chamber 420 to establish within chamber 420 an aseptic condition;
and disengaging and removing the fill needle from fill needle
sheath 503'. The method may further comprise engaging the fill
needle with fill needle sheath 503' after removing terminal
pharmaceutical fluid portion 704a, 704b, 704c, 704d, 704e, 704f
from the fill needle.
[0158] FIG. 24 shows an implementation of a fill needle system
employing, by way of example, fill needle 414' of aseptically
sealed fill needle package 900 shown in FIGS. 9A, 9B and 9C. Fill
needle 414' comprises fill needle tubing 501' and fill needle hub
502'. Fill needle tubing 501' is in fluid communication with
pharmaceutical fluid source, for example container 401 of FIG. 1,
via flexible tubing 405 and extending through fill needle hub 502',
fill needle 414' having fill needle dispensing tip 506' disposed at
a dispensing end of fill needle tubing 405. Any other fill needle
suitable for filling containers with pharmaceutical fluid 702 may
be employed, including fill needle 414 of FIG.1 and FIG.2. As
already described at the hand of FIG.1, flexible tubing 405 enters
chamber 420 via an aseptically sealing flange (not shown), so that
the exterior of fluid path 404 within chamber 420 is aseptically
sealed with respect to the interior of chamber 420. Pump 410 urges
the fluid in question along fluid path 404 within flexible tubing
405. None of the elements of FIG. 24 is drawn to scale.
[0159] Fluid pressure pulse induction system 406, shown
schematically in FIG.24, is disposed along fluid path 404 and
arranged and configured to induce a fluid pressure pulse in the
fluid within flexible tubing 405 at the end of a filling cycle.
This fluid pressure pulse ensures that any droplet of fluid 704g
remaining at the tip of fill needle tubing 501' at the end of a
filling cycle is ejected into a container being filled with the
fluid provided by pump 410 along fluid path 404 through flexible
tubing 405. By suitable adjustment of pressure pulse induction
system 406, the fluid pressure pulse may be calibrated and set to
dislodge only fluid droplet 704g and no further droplets of
fluid.
[0160] Different embodiments of fluid pressure pulse induction
system 406 are contemplated. In FIG. 24, two pressure members 407a
and 407b are shown. These two pressure members may be actuated by
different means to move as indicated by arrows 408a and 408b
respectively, as indicated in FIG.24. In other embodiments, one of
member 407a and member 407b may be stationary, and the other of
member 407a and member 407b may move as indicated when actuated. In
either of these embodiments, flexible tubing 405 is compressed
between pressure members 407a and 407b to induce a fluid pressure
pulse in the fluid within flexible tubing 405. Any one or more of
the force on members 407a and 407b; the duration of the pressure
pulse; the length of tubing 405 compressed; the geometrical shapes
pressure members 407a and 407b; and the angle at which members 407a
and 407b close tubing 405 may be adapted to produce a desired
amplitude and duration of pulse.
[0161] Actuation of pressure members 407a and/or 407b may be by
electro-mechanical means, by pneumatic means, by magnetic induction
transducer, piezoelectric transducer or any other means that will
compress flexible tubing 405 in a controllable, repeatable and
calibratable fashion. Any of the fluid pressure pulse induction
systems 406 described herein may be controlled by controller 440 of
FIG. 1. Controller 440 may be preprogrammed to produce via fluid
pressure pulse induction system 406 a predetermined fluid pressure
pulse amplitude and duration within fill needle tubing 501'. The
predetermined fluid pressure pulse amplitude and duration within
fill needle tubing 501' may be selected to specifically dislodge
only a single droplet 704 of pharmaceutical fluid retained on
dispensing tip 506' after halting the dispensing.
[0162] In other embodiments of fluid pressure pulse induction
system 406, more than two pressure members may be employed to
compress flexible tubing 405. In yet further embodiments of fluid
pressure pulse induction system 406, a pressure member may be
arranged to contract annularly around flexible tubing 405. To this
end, as shown in FIG. 25, flexible tubing 405 may be routed through
a piezoelectrically activated tube 407'. Application of an
actuating voltage to piezoelectrically activated tube 407' causes
tube 407' to contract annularly, as shown by the arrows, thereby
inducing a fluid pressure pulse in flexible tubing 405.
[0163] Fluid pressure pulse induction system 406 may be disposed
along fluid path 404 outside chamber 420 in order to minimize the
number of moving parts inside chamber 420 that may potentially
contribute to dust and debris creation in chamber 420.
[0164] In another aspect, described at the hand of the flow chart
shown in FIG. 26, method 2400 is provided for aseptically filling
pharmaceutical container 411 with pharmaceutical fluid 702 using
the fill needle system of FIG. 24, the method comprising: in
chamber 420 (See FIG. 1) capable of maintaining an aseptic
condition providing [2410] a fill needle system comprising fill
needle 414', fill needle 414' comprising fill needle tubing 501' in
fluid communication with dispensing tip 506'; establishing [2420]
in chamber 420 an aseptic condition; providing [2430] in chamber
420 at least one aseptic pharmaceutical container 411 comprising a
container opening; dispensing [2440] pharmaceutical fluid 702
through dispensing tip 506' and the container opening into the at
least one container 411; halting [2450] dispensing to retain on
dispensing tip 506' pharmaceutical fluid droplet 704g; and inducing
[2460] a pressure pulse in fluid 702 in fill needle tubing 501' to
dislodge droplet 704g from dispensing tip 506 into container 411.
The method may further comprise providing a controller, for example
controller 440 of FIG. 1. Halting [2450] dispensing and inducing
[2460] a pressure pulse may be automatically controlled by
controller 440.
[0165] Providing [2410] the fill needle system may comprise
providing a fluid pressure pulse induction system 406 and flexible
tubing 405 in fluid communication with fill needle tubing 501' and
dispensing tip 506', wherein the pressure pulse induction system
406 is disposed and configured to compress flexible tubing 405.
Inducing [2460] a pressure pulse in fluid 702 may comprise
operating fluid pressure pulse induction system 406 to compress
flexible tubing 405. Compressing flexible tubing 405 may comprise
annularly compressing flexible tubing 405.
[0166] Dispensing [2440] pharmaceutical fluid 702 may comprise
moving at least one of fill needle 414' and the at least one
container 411 to dispose fill needle 414' over the container
opening.
[0167] Providing [2410] the fill needle system may further comprise
providing a first robotic arm, for example robotic arm 415 of FIG.
1, having a first end effector, for example end effector 1100 of
FIG. 14B. Moving fill needle 14' may comprise engaging fill needle
414' with first end effector 1100 and operating robotic arm 415.
Providing a first robotic arm may comprise providing first
articulated robotic arm 415.
[0168] Providing [2430] at least one container 411 may comprise
providing a container nest bearing the at least one container 411.
Providing the container nest may further comprise providing a
second robotic arm having a second end effector; and moving the at
least one container 411 may comprise engaging the container nest
with the second end effector and operating the second robotic arm.
Providing the second robotic arm may comprise providing a second
articulated robotic arm. FIG. 9 of United States Patent Publication
US 2018-0282008 A1, herein incorporated in full, shows containers
510 in a nest 500 and nest 500 is moved by an articulated robotic
arm 800, which serves as second robotic arm in the present
specification. In another embodiment, providing the container nest
may comprise providing the container nest held in a locating
structure of a rotary stage, and moving the at least one container
may comprise rotating the rotary stage. Suitable rotary stages for
holding and moving nests of containers are described in detail in
United States Patent Publications US 2018-0072446 A1 (published
Mar. 15, 2018), US 2018-0071168 A1 (published Mar. 15, 2018), and
US 2018-0282008 A1 (published Oct. 4, 2018), and PCT International
Patent Publication WO/2018/049516 (published Mar. 22, 2018), all of
which are herein incorporated in full.
[0169] Providing [2410] the fill needle may comprise providing the
fill needle closed with a fill needle sheath, for example fill
needle sheath 503' of FIG. 9A; sterilizing chamber 420 to establish
within chamber 420 an aseptic condition; and disengaging and
removing fill needle 414' from fill needle sheath 503'. The method
may further comprise engaging fill needle 414' with fill needle
sheath 503' after automatically dislodging pharmaceutical fluid
droplet 704g from fill needle 414' into container 411.
Additional Notes
[0170] The above detailed description includes references to the
accompanying drawings, which form a part of the detailed
description. The drawings show, by way of illustration, specific
embodiments in which the invention may be practiced. These
embodiments are also referred to herein as "examples." All
publications, patents, and patent documents referred to in this
document are incorporated by reference herein in their entirety, as
though individually incorporated by reference. In the event of
inconsistent usages between this document and those documents so
incorporated by reference, the usage in the incorporated
reference(s) should be considered supplementary to that of this
document; for irreconcilable inconsistencies, the usage in this
document controls.
[0171] In this document, the terms "a" or "an" are used, as is
common in patent documents, to include one or more than one,
independent of any other instances or usages of "at least one" or
"one or more." In this document, the term "or" is used to refer to
a nonexclusive or, such that "A or B" includes "A but not B," "B
but not A," and "A and B," unless otherwise indicated. In the
appended claims, the terms "including" and "in which" are used as
the plain-English equivalents of the respective terms "comprising"
and "wherein." Also, in the following claims, the terms "including"
and "comprising" are open-ended, that is, a system, device,
article, or process that includes elements in addition to those
listed after such a term in a claim are still deemed to fall within
the scope of that claim. Moreover, in the following claims, the
terms "first," "second," and "third," etc. are used merely as
labels, and are not intended to impose numerical requirements on
their objects.
[0172] Method examples described herein may be machine or
computer-implemented at least in part. Some examples may include a
tangible computer-readable medium or machine-readable medium
encoded with instructions operable to configure an electronic
device to perform methods as described in the above examples. An
implementation of such methods may include code, such as microcode,
assembly language code, a higher-level language code, or the like.
Such code may include computer readable instructions for performing
various methods. The code may form portions of computer program
products. Further, the code may be tangibly stored on one or more
volatile or non-volatile computer-readable media during execution
or at other times. These computer-readable media may include, but
are not limited to, hard disks, removable magnetic disks, removable
optical disks (e.g., compact disks and digital video disks),
magnetic cassettes, memory cards or sticks, random access memories
(RAM's), read only memories (ROM's), and the like.
[0173] The above description is intended to be illustrative, and
not restrictive. For example, the above-described examples (or one
or more aspects thereof) may be used in combination with each
other. Other embodiments may be used, such as by one of ordinary
skill in the art upon reviewing the above description. The Abstract
is provided to comply with 37 C.F.R. .sctn. 1.72(b), to allow the
reader to quickly ascertain the nature of the technical disclosure.
It is submitted with the understanding that it will not be used to
interpret or limit the scope or meaning of the claims. Also, in the
above Detailed Description, various features may be grouped
together to streamline the disclosure. This should not be
interpreted as intending that an unclaimed disclosed feature is
essential to any claim. Rather, inventive subject matter may lie in
less than all features of a particular disclosed embodiment. Thus,
the following claims are hereby incorporated into the Detailed
Description, with each claim standing on its own as a separate
embodiment. The scope of the invention should be determined with
reference to the appended claims, along with the full scope of
equivalents to which such claims are entitled.
* * * * *